TY - JOUR AB - Sexual dimorphism involves distinct anatomical, physiological, behavioral, and developmental differences between males and females of the same species, influenced by factors prior to conception and during early development. These sex-specific traits contribute to varied phenotypes and individual disease risks within and across generations and understanding them is essential in mammalian studies. Hormones, sex chromosomes, and imprinted genes drive this dimorphism, with over half of quantitative traits in wildtype mice showing sex-based variation. This review focuses on the impact of paternal non-genetic factors on sexual dimorphism. We synthesize current research on how paternal health before conception affects offspring phenotypes in a sex-specific manner, examining mechanisms such as DNA methylation, paternally imprinted genes, sperm RNA, and seminal plasma. Additionally, we explore how paternal influences indirectly shape offspring through maternal behavior, uterine environment, and placental changes, affecting males and females differently. We propose mechanisms modulating sexual dimorphism during development, underscoring the need for sex-specific documentation in animal studies. AU - Aljabali, S. M. AU - Pai, S. AU - Teperino, R. C1 - 72866 C2 - 56749 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Paternal impact on the developmental programming of sexual dimorphism. JO - Front. Cell Dev. Biol. VL - 12 PB - Frontiers Media Sa PY - 2024 SN - 2296-634X ER - TY - JOUR AB - Spermatogenesis is a crucial biological process that enables the production of functional sperm, allowing for successful reproduction. Proper germ cell differentiation and maturation require tight regulation of hormonal signals, cellular signaling pathways, and cell biological processes. The acrosome is a lysosome-related organelle at the anterior of the sperm head that contains enzymes and receptors essential for egg-sperm recognition and fusion. Even though several factors crucial for acrosome biogenesis have been discovered, the precise molecular mechanism of pro-acrosomal vesicle formation and fusion is not yet known. In this study, we investigated the role of the insulin inhibitory receptor (inceptor) in acrosome formation. Inceptor is a single-pass transmembrane protein with similarities to mannose-6-phosphate receptors (M6PR). Inceptor knockout male mice are infertile due to malformations in the acrosome and defects in the nuclear shape of spermatozoa. We show that inceptor is expressed in early spermatids and mainly localizes to vesicles between the Golgi apparatus and acrosome. Here we show that inceptor is an essential factor in the intracellular transport of trans-Golgi network-derived vesicles which deliver acrosomal cargo in maturing spermatids. The absence of inceptor results in vesicle-fusion defects, acrosomal malformation, and male infertility. These findings support our hypothesis of inceptor as a universal lysosomal or lysosome-related organelle sorting receptor expressed in several secretory tissues. AU - Bilekova, S. AU - Garcia-Colomer, B. AU - Cebrian Serrano, A. AU - Schirge, S. AU - Krey, K.* AU - Sterr, M. AU - Kurth, T.* AU - Hauck, S.M. AU - Lickert, H. C1 - 68314 C2 - 54713 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Inceptor facilitates acrosomal vesicle formation in spermatids and is required for male fertility. JO - Front. Cell Dev. Biol. VL - 11 PB - Frontiers Media Sa PY - 2023 SN - 2296-634X ER - TY - JOUR AU - Lee, K.Y.* AU - Emanuelli, B.* AU - Ussar, S. C1 - 68649 C2 - 54852 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Editorial: Healthy adipose tissue expansion. JO - Front. Cell Dev. Biol. VL - 11 PB - Frontiers Media Sa PY - 2023 SN - 2296-634X ER - TY - JOUR AB - Normal function of the C-terminal Eps15 homology domain-containing protein 1 (EHD1) has previously been associated with endocytic vesicle trafficking, shaping of intracellular membranes, and ciliogenesis. We recently identified an autosomal recessive missense mutation c.1192C>T (p.R398W) of EHD1 in patients who had low molecular weight proteinuria (0.7-2.1 g/d) and high-frequency hearing loss. It was already known from Ehd1 knockout mice that inactivation of Ehd1 can lead to male infertility. However, the exact role of the EHD1 protein and its p.R398W mutant during spermatogenesis remained still unclear. Here, we report the testicular phenotype of a knockin mouse model carrying the p.R398W mutation in the EHD1 protein. Male homozygous knockin mice were infertile, whereas the mutation had no effect on female fertility. Testes and epididymes were significantly reduced in size and weight. The testicular epithelium appeared profoundly damaged and had a disorganized architecture. The composition of developing cell types was altered. Malformed acrosomes covered underdeveloped and misshaped sperm heads. In the sperm tail, midpieces were largely missing indicating disturbed assembly of the sperm tail. Defective structures, i.e., nuclei, acrosomes, and sperm tail midpieces, were observed in large vacuoles scattered throughout the epithelium. Interestingly, cilia formation itself did not appear to be affected, as the axoneme and other parts of the sperm tails except the midpieces appeared to be intact. In wildtype mice, EHD1 co-localized with acrosomal granules on round spermatids, suggesting a role of the EHD1 protein during acrosomal development. Wildtype EHD1 also co-localized with the VPS35 component of the retromer complex, whereas the p.R398W mutant did not. The testicular pathologies appeared very early during the first spermatogenic wave in young mice (starting at 14 dpp) and tubular destruction worsened with age. Taken together, EHD1 plays an important and probably multifaceted role in spermatogenesis in mice. Therefore, EHD1 may also be a hitherto underestimated infertility gene in humans. AU - Meindl, K.* AU - Issler, N.* AU - Afonso, S.* AU - Cebrian Serrano, A. AU - Müller, K.* AU - Sterner, C.* AU - Othmen, H.* AU - Tegtmeier, I.* AU - Witzgall, R.* AU - Klootwijk, E.* AU - Davies, B.* AU - Kleta, R.* AU - Warth, R.* C1 - 68742 C2 - 54952 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - A missense mutation in Ehd1 associated with defective spermatogenesis and male infertility. JO - Front. Cell Dev. Biol. VL - 11 PB - Frontiers Media Sa PY - 2023 SN - 2296-634X ER - TY - JOUR AB - The Hawaiian bobtail squid, Euprymna scolopes, harvests its luminous symbiont, Vibrio fischeri, from the surrounding seawater within hours of hatching. During embryogenesis, the host animal develops a nascent light organ with ciliated fields on each lateral surface. We hypothesized that these fields function to increase the efficiency of symbiont colonization of host tissues. Within minutes of hatching from the egg, the host's ciliated fields shed copious amounts of mucus in a non-specific response to bacterial surface molecules, specifically peptidoglycan (PGN), from the bacterioplankton in the surrounding seawater. Experimental manipulation of the system provided evidence that nitric oxide in the mucus drives an increase in ciliary beat frequency (CBF), and exposure to even small numbers of V. fischeri cells for short periods resulted in an additional increase in CBF. These results indicate that the light-organ ciliated fields respond specifically, sensitively, and rapidly, to the presence of nonspecific PGN as well as symbiont cells in the ambient seawater. Notably, the study provides the first evidence that this induction of an increase in CBF occurs as part of a thus far undiscovered initial phase in colonization of the squid host by its symbiont, i.e., host recognition of V. fischeri cues in the environment within minutes. Using a biophysics-based mathematical analysis, we showed that this rapid induction of increased CBF, while accelerating bacterial advection, is unlikely to be signaled by V. fischeri cells interacting directly with the organ surface. These overall changes in CBF were shown to significantly impact the efficiency of V. fischeri colonization of the host organ. Further, once V. fischeri has fully colonized the host tissues, i.e., about 12-24 h after initial host-symbiont interactions, the symbionts drove an attenuation of mucus shedding from the ciliated fields, concomitant with an attenuation of the CBF. Taken together, these findings offer a window into the very first interactions of ciliated surfaces with their coevolved microbial partners. AU - Gundlach, K.A.* AU - Nawroth, J. AU - Kanso, E.* AU - Nasrin, F.* AU - Ruby, E.G.* AU - McFall-Ngai, M.* C1 - 66601 C2 - 53236 TI - Ciliated epithelia are key elements in the recruitment of bacterial partners in the squid-vibrio symbiosis. JO - Front. Cell Dev. Biol. VL - 10 PY - 2022 SN - 2296-634X ER - TY - JOUR AB - Aging is a complex process characterized by several molecular and cellular imbalances. The composition and stability of the neuronal cytoskeleton is essential for the maintenance of homeostasis, especially in long neurites. Using human skin biopsies containing sensory axons from a cohort of healthy individuals, we investigate alterations in cytoskeletal content and sensory axon caliber during aging via quantitative immunostainings. Cytoskeletal components show an increase with aging in both sexes, while elevation in axon diameter is only evident in males. Transcriptomic data from aging males illustrate various patterns in gene expression during aging. Together, the data suggest gender-specific changes during aging in peripheral sensory axons, possibly influencing cytoskeletal functionality and axonal caliber. These changes may cumulatively increase susceptibility of aged individuals to neurodegenerative diseases. AU - Metzner, K.J.* AU - Darawsha, O.* AU - Wang, M.* AU - Gaur, N.* AU - Cheng, Y. AU - Rödiger, A.* AU - Frahm, C.* AU - Witte, O.W.* AU - Perocchi, F. AU - Axer, H.* AU - Grosskreutz, J.* AU - Brill, M.S.* C1 - 66734 C2 - 53285 TI - Age-dependent increase of cytoskeletal components in sensory axons in human skin. JO - Front. Cell Dev. Biol. VL - 10 PY - 2022 SN - 2296-634X ER - TY - JOUR AB - In humans, various dietary and social factors led to the development of increased brain sizes alongside large adipose tissue stores. Complex reciprocal signaling mechanisms allow for a fine-tuned interaction between the two organs to regulate energy homeostasis of the organism. As an endocrine organ, adipose tissue secretes various hormones, cytokines, and metabolites that signal energy availability to the central nervous system (CNS). Vice versa, the CNS is a critical regulator of adipose tissue function through neural networks that integrate information from the periphery and regulate sympathetic nerve outflow. This review discusses the various reciprocal signaling mechanisms in the CNS and adipose tissue to maintain organismal energy homeostasis. We are focusing on the integration of afferent signals from the periphery in neuronal populations of the mediobasal hypothalamus as well as the efferent signals from the CNS to adipose tissue and its implications for adipose tissue function. Furthermore, we are discussing central mechanisms that fine-tune the immune system in adipose tissue depots and contribute to organ homeostasis. Elucidating this complex signaling network that integrates peripheral signals to generate physiological outputs to maintain the optimal energy balance of the organism is crucial for understanding the pathophysiology of obesity and metabolic diseases such as type 2 diabetes. AU - Puente-Ruiz, S.C. AU - Jais, A. C1 - 66348 C2 - 52773 TI - Reciprocal signaling between adipose tissue depots and the central nervous system. JO - Front. Cell Dev. Biol. VL - 10 PY - 2022 SN - 2296-634X ER - TY - JOUR AB - STAG2 is a component of the large, evolutionarily highly conserved cohesin complex, which has been linked to various cellular processes like genome organization, DNA replication, gene expression, heterochromatin formation, sister chromatid cohesion, and DNA repair. A wide spectrum of germline variants in genes encoding subunits or regulators of the cohesin complex have previously been identified to cause distinct but phenotypically overlapping multisystem developmental disorders belonging to the group of cohesinopathies. Pathogenic variants in STAG2 have rarely been implicated in an X-linked cohesinopathy associated with undergrowth, developmental delay, and dysmorphic features. Here, we describe for the first time a mosaic STAG2 variant in an individual with developmental delay, microcephaly, and hemihypotrophy of the right side. We characterized the grade of mosaicism by deep sequencing analysis on DNA extracted from EDTA blood, urine and buccal swabs. Furthermore, we report an additional female with a novel de novo splice variant in STAG2. Interestingly, both individuals show supernumerary nipples, a feature that has not been reported associated to STAG2 before. Remarkably, additional analysis of STAG2 transcripts in both individuals showed only wildtype transcripts, even after blockage of nonsense-mediated decay using puromycin in blood lymphocytes. As the phenotype of STAG2-associated cohesinopathies is dominated by global developmental delay, severe microcephaly, and brain abnormalities, we investigated the expression of STAG2 and other related components of the cohesin complex during Bioengineered Neuronal Organoids (BENOs) generation by RNA sequencing. Interestingly, we observed a prominent expression of STAG2, especially between culture days 0 and 15, indicating an essential function of STAG2 in early brain development. In summary, we expand the genotypic and phenotypic spectrum of STAG2-associated cohesinopathies and show that BENOs represent a promising model to gain further insights into the critical role of STAG2 in the complex process of nervous system development. AU - Schmidt, J.* AU - Dreha-Kulaczewski, S.* AU - Zafeiriou, M.P.* AU - Schreiber, M.K.* AU - Wilken, B.* AU - Funke, R.* AU - Neuhofer, C. AU - Altmüller, J.* AU - Thiele, H.* AU - Nürnberg, P.* AU - Biskup, S.* AU - Li, Y.* AU - Zimmermann, W.H.* AU - Kaulfuß, S.* AU - Yigit, G.* AU - Wollnik, B.* C1 - 66924 C2 - 53351 TI - Somatic mosaicism in STAG2-associated cohesinopathies: Expansion of the genotypic and phenotypic spectrum. JO - Front. Cell Dev. Biol. VL - 10 PY - 2022 SN - 2296-634X ER - TY - JOUR AB - Besides the basic organization in nucleosome core particles (NCPs), eukaryotic chromatin is further packed through interactions with numerous protein complexes including transcription factors, chromatin remodeling and modifying enzymes. This nucleoprotein complex provides the template for many important biological processes, such as DNA replication, transcription, and DNA repair. Thus, to understand the molecular basis of these DNA transactions, it is critical to define individual changes of the chromatin structure at precise genomic regions where these machineries assemble and drive biological reactions. Single-molecule approaches provide the only possible solution to overcome the heterogenous nature of chromatin and monitor the behavior of individual chromatin transactions in real-time. In this review, we will give an overview of currently available single-molecule methods to obtain mechanistic insights into nucleosome positioning, histone modifications and DNA replication and transcription analysis-previously unattainable with population-based assays. AU - Chanou, A. AU - Hamperl, S. C1 - 62642 C2 - 50969 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Single-molecule techniques to study chromatin. JO - Front. Cell Dev. Biol. VL - 9 PB - Frontiers Media Sa PY - 2021 SN - 2296-634X ER - TY - JOUR AB - Growing evidence suggests that epigenetic mechanisms like microRNA-mediated transcriptional regulation contribute to the pathogenesis of parkinsonism. In order to study the influence of microRNAs (miRNAs), we analyzed the miRNome 2 days prior to major cell death in alpha-synuclein-overexpressing Lund human mesencephalic neurons, a well-established cell model of Parkinson's disease (PD), by next-generation sequencing. The expression levels of 23 miRNAs were significantly altered in alpha-synuclein-overexpressing cells, 11 were down- and 12 upregulated (P < 0.01; non-adjusted). The in silico analysis of known target genes of these miRNAs was complemented by the inclusion of a transcriptome dataset (BeadChip) of the same cellular system, revealing the G0/G1 cell cycle transition to be markedly enriched. Out of 124 KEGG-annotated cell cycle genes, 15 were present in the miRNA target gene dataset and six G0/G1 cell cycle genes were found to be significantly altered upon alpha-synuclein overexpression, with five genes up- (CCND1, CCND2, and CDK4 at P < 0.01; E2F3, MYC at P < 0.05) and one gene downregulated (CDKN1C at P < 0.001). Additionally, several of these altered genes are targeted by miRNAs hsa-miR-34a-5p and hsa-miR-34c-5p, which also modulate alpha-synuclein expression levels. Functional intervention by siRNA-mediated knockdown of the cell cycle gene cyclin D1 (CCND1) confirmed that silencing of cell cycle initiation is able to substantially reduce alpha-synuclein-mediated cytotoxicity. The present findings suggest that alpha-synuclein accumulation induces microRNA-mediated aberrant cell cycle activation in post-mitotic dopaminergic neurons. Thus, the mitotic cell cycle pathway at the level of miRNAs might offer interesting novel therapeutic targets for PD. AU - Findeiss, E.* AU - Schwarz, S.C.* AU - Evsyukov, V.* AU - Roesler, T.W.* AU - Hoellerhage, M.* AU - Chakroun, T.* AU - Nykaenen, N.* AU - Shen, Y.* AU - Wurst, W. AU - Kohl, M.* AU - Tost, J.* AU - Hoeglinger, G.U.* C1 - 61650 C2 - 50135 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Comprehensive miRNome-wide profiling in a neuronal cell model of synucleinopathy implies involvement of cell cycle genes. JO - Front. Cell Dev. Biol. VL - 9 PB - Frontiers Media Sa PY - 2021 SN - 2296-634X ER - TY - JOUR AB - Human PEX5 and PEX14 are essential components of the peroxisomal translocon, which mediates import of cargo enzymes into peroxisomes. PEX5 is a soluble receptor for cargo enzymes comprised of an N-terminal intrinsically disordered domain (NTD) and a C-terminal tetratricopeptide (TPR) domain, which recognizes peroxisomal targeting signal 1 (PTS1) peptide motif in cargo proteins. The PEX5 NTD harbors multiple WF peptide motifs (WxxxF/Y or related motifs) that are recognized by a small globular domain in the NTD of the membrane-associated protein PEX14. How the PEX5 or PEX14 NTDs bind to the peroxisomal membrane and how the interaction between the two proteins is modulated at the membrane is unknown. Here, we characterize the membrane interactions of the PEX5 NTD and PEX14 NTD in vitro by membrane mimicking bicelles and nanodiscs using NMR spectroscopy and isothermal titration calorimetry. The PEX14 NTD weakly interacts with membrane mimicking bicelles with a surface that partially overlaps with the WxxxF/Y binding site. The PEX5 NTD harbors multiple interaction sites with the membrane that involve a number of amphipathic alpha-helical regions, which include some of the WxxxF/Y-motifs. The partially formed alpha-helical conformation of these regions is stabilized in the presence of bicelles. Notably, ITC data show that the interaction between the PEX5 and PEX14 NTDs is largely unaffected by the presence of the membrane. The PEX5/PEX14 interaction exhibits similar free binding enthalpies, where reduced binding enthalpy in the presence of bicelles is compensated by a reduced entropy loss. This demonstrates that docking of PEX5 to PEX14 at the membrane does not reduce the overall binding affinity between the two proteins, providing insights into the initial phase of PEX5-PEX14 docking in the assembly of the peroxisome translocon. AU - Gaussmann, S. AU - Gopalswamy, M. AU - Eberhardt, M. AU - Reuter, M.* AU - Zou, P. AU - Schliebs, W.* AU - Erdmann, R.* AU - Sattler, M. C1 - 61917 C2 - 50424 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Membrane interactions of the peroxisomal proteins PEX5 and PEX14. JO - Front. Cell Dev. Biol. VL - 9 PB - Frontiers Media Sa PY - 2021 SN - 2296-634X ER - TY - JOUR AB - Augmenter of liver regeneration (ALR) is a critical multi-isoform protein with its longer isoform, located in the mitochondrial intermembrane space, being part of the mitochondrial disulfide relay system (DRS). Upregulation of ALR was observed in multiple forms of cancer, among them hepatocellular carcinoma (HCC). To shed light into ALR function in HCC, we used MitoBloCK-6 to pharmacologically inhibit ALR, resulting in profound mitochondrial impairment and cancer cell proliferation deficits. These effects were mostly reversed by supplementation with bioavailable hemin b, linking ALR function to mitochondrial iron homeostasis. Since many tumor cells are known for their increased iron demand and since increased iron levels in cancer are associated with poor clinical outcome, these results help to further advance the intricate relation between iron and mitochondrial homeostasis in liver cancer. AU - Kabiri, Y.* AU - Fuhrmann, A. AU - Becker, A. AU - Jedermann, L. AU - Eberhagen, C. AU - König, A. AU - Silva, T.B.* AU - Borges, F.* AU - Hauck, S.M. AU - Michalke, B. AU - Knolle, P.* AU - Zischka, H. C1 - 63234 C2 - 51237 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Mitochondrial impairment by MitobloCK-6 inhibits liver cancer cell proliferation.  JO - Front. Cell Dev. Biol. VL - 9 PB - Frontiers Media Sa PY - 2021 SN - 2296-634X ER - TY - JOUR AB - Human pathogenic trypanosomatid parasites harbor a unique form of peroxisomes termed glycosomes that are essential for parasite viability. We and others previously identified and characterized the essential Trypanosoma brucei ortholog TbPEX3, which is the membrane-docking factor for the cytosolic receptor PEX19 bound to the glycosomal membrane proteins. Knockdown of TbPEX3 expression leads to mislocalization of glycosomal membrane and matrix proteins, and subsequent cell death. As an early step in glycosome biogenesis, the PEX3–PEX19 interaction is an attractive drug target. We established a high-throughput assay for TbPEX3–TbPEX19 interaction and screened a compound library for small-molecule inhibitors. Hits from the screen were further validated using an in vitro ELISA assay. We identified three compounds, which exhibit significant trypanocidal activity but show no apparent toxicity to human cells. Furthermore, we show that these compounds lead to mislocalization of glycosomal proteins, which is toxic to the trypanosomes. Moreover, NMR-based experiments indicate that the inhibitors bind to PEX3. The inhibitors interfering with glycosomal biogenesis by targeting the TbPEX3–TbPEX19 interaction serve as starting points for further optimization and anti-trypanosomal drug development. AU - Li, M.* AU - Gaussmann, S. AU - Tippler, B.* AU - Ott, J.J.* AU - Popowicz, G.M. AU - Schliebs, W.* AU - Sattler, M. AU - Erdmann, R.* AU - Kalel, V.C.* C1 - 63951 C2 - 51701 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Novel trypanocidal inhibitors that block glycosome biogenesis by targeting PEX3–PEX19 interaction. JO - Front. Cell Dev. Biol. VL - 9 PB - Frontiers Media Sa PY - 2021 SN - 2296-634X ER - TY - JOUR AB - TBL1XR1 gene is associated with multiple developmental disorders presenting several neurological aspects. The relative protein is involved in the modulation of important cellular pathways and master regulators of transcriptional output, including nuclear receptor repressors, Wnt signaling, and MECP2 protein. However, TBL1XR1 mutations (including complete loss of its functions) have not been experimentally studied in a neurological context, leaving a knowledge gap in the mechanisms at the basis of the diseases. Here, we show that Tbl1xr1 knock-out mice exhibit behavioral and neuronal abnormalities. Either the absence of TBL1XR1 or its point mutations interfering with stability/regulation of NCOR complex induced decreased proliferation and increased differentiation in neural progenitors. We suggest that this developmental unbalance is due to a failure in the regulation of the MAPK cascade. Taken together, our results broaden the molecular and functional aftermath of TBL1XR1 deficiency associated with human disorders. AU - Mastrototaro, G.* AU - Zaghi, M.* AU - Massimino, L.* AU - Moneta, M.* AU - Mohammadi, N.* AU - Banfi, F.* AU - Bellini, E.* AU - Indrigo, M.* AU - Fagnocchi, G.* AU - Bagliani, A.* AU - Taverna, S.* AU - Rohm, M. AU - Herzig, S. AU - Sessa, A.* C1 - 61548 C2 - 49912 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - TBL1XR1 ensures balanced neural development through NCOR complex-mediated regulation of the MAPK pathway. JO - Front. Cell Dev. Biol. VL - 9 PB - Frontiers Media Sa PY - 2021 SN - 2296-634X ER - TY - JOUR AB - Long noncoding RNAs (lncRNAs) are regulatory molecules which have been traditionally considered as "non-coding". Strikingly, recent evidence has demonstrated that many non-coding regions, including lncRNAs, do in fact contain small-open reading frames that code for small proteins that have been called microproteins. Only a few of them have been characterized so far, but they display key functions in a wide variety of cellular processes. Here, we show that TUNAR lncRNA encodes an evolutionarily conserved microprotein expressed in the nervous system that we have named pTUNAR. pTUNAR deficiency in mouse embryonic stem cells improves their differentiation potential towards neural lineage both in vitro and in vivo. Conversely, pTUNAR overexpression impairs neuronal differentiation by reduced neurite formation in different model systems. At the subcellular level, pTUNAR is a transmembrane protein that localizes in the endoplasmic reticulum and interacts with the calcium transporter SERCA2. pTUNAR overexpression reduces cytoplasmatic calcium, consistent with a possible role of pTUNAR as an activator of SERCA2. Altogether, our results suggest that our newly discovered microprotein has an important role in neural differentiation and neurite formation through the regulation of intracellular calcium. From a more general point of view, our results provide a proof of concept of the role of lncRNAs-encoded microproteins in neural differentiation. AU - Senís, E.* AU - Esgleas Izquierdo, M. AU - Najas, S. AU - Jiménez-Sábado, V.* AU - Bertani, C.* AU - Giménez-Alejandre, M.* AU - Escriche, A.* AU - Ruiz-Orera, J.* AU - Hergueta-Redondo, M.* AU - Jimenez, M.* AU - Giralt, A.* AU - Nuciforo, P.* AU - Albà, M.M.* AU - Peinado, H.* AU - Del Toro, D.* AU - Hove-Madsen, L.* AU - Götz, M. AU - Abad, M.* C1 - 64134 C2 - 51688 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - TUNAR lncRNA encodes a microprotein that regulates neural differentiation and neurite formation by modulating calcium dynamics. JO - Front. Cell Dev. Biol. VL - 9 PB - Frontiers Media Sa PY - 2021 SN - 2296-634X ER - TY - JOUR AB - The H1 haplotype of the microtubule-associated protein tau (MAPT) gene is a common genetic risk factor for some neurodegenerative diseases such as progressive supranuclear palsy, corticobasal degeneration, and Parkinson’s disease. The molecular mechanism causing the increased risk for the named diseases, however, remains unclear. In this paper, we present a valuable tool of eight small molecule neural precursor cell lines (smNPC) homozygous for the MAPT haplotypes (four H1/H1 and four H2/H2 cell lines), which can be used to identify MAPT-dependent phenotypes. The employed differentiation protocol is fast due to overexpression of NEUROGENIN-2 and therefore suitable for high-throughput approaches. A basic characterization of all human cell lines was performed, and their TAU and α-SYNUCLEIN profiles were compared during a differentiation time of 30 days. We could identify higher levels of conformationally altered TAU in cell lines carrying the H2 haplotype. Additionally, we found increased expression levels of α-SYNUCLEIN in H1/H1 cells. With this resource, we aim to fill a gap in neurodegenerative disease modeling with induced pluripotent stem cells (iPSC) for sporadic tauopathies. AU - Strauß, T.* AU - Marvian-Tayaranian, A.* AU - Sadikoglou, E.* AU - Dhingra, A.* AU - Wegner, F.* AU - Trümbach, D. AU - Wurst, W. AU - Heutink, P.* AU - Schwarz, S.C.* AU - Höglinger, G.U.* C1 - 63018 C2 - 51214 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - iPS cell-based model for MAPT Haplotype as a risk factor for human tauopathies identifies no major differences in TAU expression. JO - Front. Cell Dev. Biol. VL - 9 PB - Frontiers Media Sa PY - 2021 SN - 2296-634X ER - TY - JOUR AB - In this perspective article, we briefly review tools for stable gain-of-function expression to explore key fate determinants in embryonic brain development. As the piggyBac transposon system has the highest insert size, a seamless integration of the transposed sequence into the host genome, and can be delivered by transfection avoiding viral vectors causing an immune response, we explored its use in the murine developing forebrain. The original piggyBac transposase PBase or the mouse codon-optimized version mPB and the construct to insert, contained in the piggyBac transposon, were introduced by in utero electroporation at embryonic day 13 into radial glia, the neural stem cells, in the developing dorsal telencephalon, and analyzed 3 or 5 days later. When using PBase, we observed an increase in basal progenitor cells, often accompanied by folding aberrations. These effects were considerably ameliorated when using the piggyBac plasmid together with mPB. While size and strength of the electroporated region was not correlated to the aberrations, integration was essential and the positive correlation to the insert size implicates the frequency of transposition as a possible mechanism. We discuss this in light of the increase in transposing endogenous viral vectors during mammalian phylogeny and their role in neurogenesis and radial glial cells. Most importantly, we aim to alert the users of this system to the phenotypes caused by non-codon optimized PBase application in vivo. AU - Vierl, F. AU - Kaur, M.* AU - Götz, M. C1 - 62839 C2 - 51095 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Non-codon optimized PiggyBac transposase induces developmental brain aberrations: A call for in vivo analysis. JO - Front. Cell Dev. Biol. VL - 9 PB - Frontiers Media Sa PY - 2021 SN - 2296-634X ER - TY - JOUR AB - In the adult brain, NG2-glia represent a cell population that responds to injury. To further investigate if, how and why NG2-glia are recruited to the injury site, we analyzed in detail the long-term reaction of NG2-glia after a lesion by time-lapse two-photon in vivo microscopy. Live imaging over several weeks of GFP-labeled NG2-glia in the stab wounded cerebral cortex revealed their fast and heterogeneous reaction, including proliferation, migration, polarization, hypertrophy, or a mixed response, while a small subset of cells remained unresponsive. At the peak of the reaction, 2-4 days after the injury, NG2-glia accumulated around and within the lesion core, overcoming the homeostatic control of their density, which normalized back to physiological conditions only 4 weeks after the insult. Genetic ablation of proliferating NG2-glia demonstrated that this accumulation contributed beneficially to wound closure. Thus, NG2-glia show a fast response to traumatic brain injury (TBI) and participate in tissue repair. AU - von Streitberg, A.* AU - Jäkel, S.* AU - Eugenin von Bernhardi, J.* AU - Straube, C.* AU - Buggenthin, F. AU - Marr, C. AU - Dimou, L.* C1 - 62091 C2 - 50643 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - NG2-glia transiently overcome their homeostatic network and contribute to wound closure after brain injury. JO - Front. Cell Dev. Biol. VL - 9 PB - Frontiers Media Sa PY - 2021 SN - 2296-634X ER - TY - JOUR AB - Cancer cells need excess energy and essential nutrients/metabolites not only to divide and proliferate but also to migrate and invade distant organs for metastasis. Fatty acid and cholesterol synthesis, considered a hallmark of cancer for anabolism and membrane biogenesis, requires citrate. We review here potential pathways in which citrate is synthesized and/or supplied to cancer cells and the impact of extracellular citrate on cancer cell metabolism and growth. Cancer cells employ different mechanisms to support mitochondrial activity and citrate synthesis when some of the necessary substrates are missing in the extracellular space. We also discuss the different transport mechanisms available for the entry of extracellular citrate into cancer cells and how citrate as a master metabolite enhances ATP production and fuels anabolic pathways. The available literature suggests that cancer cells show an increased metabolic flexibility with which they tackle changing environmental conditions, a phenomenon crucial for cancer cell proliferation and metastasis. AU - Haferkamp, S.* AU - Drexler, K.* AU - Federlin, M.* AU - Schlitt, H.J.* AU - Berneburg, M.* AU - Adamski, J. AU - Gaumann, A.* AU - Geissler, E.K.* AU - Ganapathy, V.* AU - Parkinson, E.K.* AU - Mycielska, M.E.* C1 - 60842 C2 - 49654 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Extracellular citrate fuels cancer cell metabolism and growth. JO - Front. Cell Dev. Biol. VL - 8 PB - Frontiers Media Sa PY - 2020 SN - 2296-634X ER - TY - JOUR AB - Granulation tissue formation constitutes a key step during wound healing of the skin and other organs. Granulation tissue concomitantly initiates regenerative M2 macrophages polarization, fibroblast proliferation, myofibroblast differentiation with subsequent contraction of the wound, new vessel formation, and matrix deposition. Impaired granulation tissue formation either leads to delayed wound healing or excessive scar formation, conditions with high morbidity and mortality. Accumulating evidence has demonstrated that mesenchymal stem cell (MSC)-based therapy is a promising strategy to ameliorate defects in granulation tissue formation and to successfully treat non-healing chronic wounds. In this review we give an updated overview of how therapeutically administered MSCs ensure a balanced granulation tissue formation, and furthermore discuss the cellular and molecular mechanisms underlying the adaptive responses of MSCs to cue in their direct neighborhood. Improved understanding of the interplay between the exogenous MSCs and their niche in granulation tissue will foster the development of MSC-based therapies tailored for difficult-to-treat non-healing wounds. AU - Jiang, D. AU - Scharffetter-Kochanek, K.* C1 - 59931 C2 - 49127 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Mesenchymal stem cells adaptively respond to environmental cues thereby improving granulation tissue formation and wound healing. JO - Front. Cell Dev. Biol. VL - 8 PB - Frontiers Media Sa PY - 2020 SN - 2296-634X ER - TY - JOUR AB - The mesodiencephalic dopaminergic (mdDA) neurons, including the nigrostriatal subset that preferentially degenerates in Parkinson's Disease (PD), strongly depend on an accurately balanced Wingless-type MMTV integration site family member 1 (WNT1)/beta-catenin signaling pathway during their development. Loss of this pathway abolishes the generation of these neurons, whereas excessive WNT1/b-catenin signaling prevents their correct differentiation. The identity of the cells responding to this pathway in the developing mammalian ventral midbrain (VM) as well as the precise progression of WNT/b-catenin action in these cells are still unknown. We show that strong WNT/b-catenin signaling inhibits the differentiation of WNT/b-catenin-responding mdDA progenitors into PITX3(+) and TH+ mdDA neurons by repressing the Pitx3 gene in mice. This effect is mediated by RSPO2, a WNT/b-catenin agonist, and lymphoid enhancer binding factor 1 (LEF1), an essential nuclear effector of the WNT/b-catenin pathway, via conserved LEF1/T-cell factor binding sites in the Pitx3 promoter. LEF1 expression is restricted to a caudolateral mdDA progenitor subset that preferentially responds to WNT/b-catenin signaling and gives rise to a fraction of all mdDA neurons. Our data indicate that an attenuation of WNT/b-catenin signaling in mdDA progenitors is essential for their correct differentiation into specific mdDA neuron subsets. This is an important consideration for stem cell-based regenerative therapies and in vitro models of neuropsychiatric diseases. AU - Nouri, P.* AU - Götz, S. AU - Rauser, B. AU - Irmler, M. AU - Peng, C. AU - Trümbach, D. AU - Kempny, C.* AU - Lechermeier, C.G. AU - Bryniok, A.* AU - Dlugos, A.* AU - Euchner, E.* AU - Beckers, J. AU - Brodski, C.* AU - Klümper, C.* AU - Wurst, W. AU - Prakash, N.* C1 - 60368 C2 - 49251 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Dose-dependent and subset-specific regulation of midbrain dopaminergic neuron differentiation by LEF1-mediated WNT1/b-catenin signaling. JO - Front. Cell Dev. Biol. VL - 8 PB - Frontiers Media Sa PY - 2020 SN - 2296-634X ER - TY - JOUR AB - Adipose progenitor cells, or preadipocytes, constitute a small population of immature cells within the adipose tissue. They are a heterogeneous group of cells, in which different subtypes have a varying degree of commitment toward diverse cell fates, contributing to white and beige adipogenesis, fibrosis or maintenance of an immature cell phenotype with proliferation capacity. Mature adipocytes as well as cells of the immune system residing in the adipose tissue can modulate the function and differentiation potential of preadipocytes in a contact- and/or paracrine-dependent manner. In the course of obesity, the accumulation of immune cells within the adipose tissue contributes to the development of a pro-inflammatory microenvironment in the tissue. Under such circumstances, the crosstalk between preadipocytes and immune or parenchymal cells of the adipose tissue may critically regulate the differentiation of preadipocytes into white adipocytes, beige adipocytes, or myofibroblasts, thereby influencing adipose tissue expansion and adipose tissue dysfunction, including downregulation of beige adipogenesis and development of fibrosis. The present review will outline the current knowledge about factors shaping cell fate decisions of adipose progenitor cells in the context of obesity-related inflammation. AU - Pyrina, I.* AU - Chung, K.J.* AU - Michailidou, Z.* AU - Koutsilieris, M.* AU - Chavakis, T. AU - Chatzigeorgiou, A.* C1 - 59835 C2 - 49063 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Fate of adipose progenitor cells in obesity-related chronic inflammation. JO - Front. Cell Dev. Biol. VL - 8 PB - Frontiers Media Sa PY - 2020 SN - 2296-634X ER - TY - JOUR AB - The concept of a mitochondrial disorder was initially described in 1962, in a patient with altered energy metabolism. Over time, mitochondrial energy metabolism has been discovered to be influenced by a vast number of proteins with a multitude of functional roles. Amongst these, defective oxidative phosphorylation arose as the hallmark of mitochondrial disorders. In the premolecular era, the diagnosis of mitochondrial disease was dependent on biochemical criteria, with inherent limitations such as tissue availability and specificity, preanalytical and analytical artifacts, and secondary effects. With the identification of the first mitochondrial disease-causing mutations, the genetic complexity of mitochondrial disorders began to unravel. Mitochondrial dysfunctions can be caused by pathogenic variants in genes encoded by the mitochondrial DNA or the nuclear DNA, and can display heterogenous phenotypic manifestations. The application of next generation sequencing methodologies in diagnostics is proving to be pivotal in finding the molecular diagnosis and has been instrumental in the discovery of a growing list of novel mitochondrial disease genes. In the molecular era, the diagnosis of a mitochondrial disorder, suspected on clinical grounds, is increasingly based on variant detection and associated statistical support, while invasive biopsies and biochemical assays are conducted to an ever-decreasing extent. At present, there is no uniform biochemical or molecular definition for the designation of a disease as a “mitochondrial disorder”. Such designation is currently dependent on the criteria applied, which may encompass clinical, genetic, biochemical, functional, and/or mitochondrial protein localization criteria. Given this variation, numerous gene lists emerge, ranging from 270 to over 400 proposed mitochondrial disease genes. Herein we provide an overview of the mitochondrial disease associated genes and their accompanying challenges. AU - Schlieben, L.D. AU - Prokisch, H. C1 - 60806 C2 - 49595 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - The dimensions of primary mitochondrial disorders. JO - Front. Cell Dev. Biol. VL - 8 PB - Frontiers Media Sa PY - 2020 SN - 2296-634X ER - TY - JOUR AB - Circular RNA (circRNA) exhibits a covalently closed circular conformation and is structurally stable. Nevertheless, the precise effects exerted by circRNA in esophageal squamous cell carcinoma (ESCC) remains uncertain. circRNA was ascertained by a human circRNA array study and was confirmed by the quantification of reverse transcriptase polymerase reactions. A luciferase reporter, fluorescence in situ hybridization experiment was exploited to explore the interaction between circ-ZDHHC5 and miR-217. The function of circ-ZDHHC5 was determined by siRNA-mediated knockout of circ-ZDHHC5 in in vitro proliferation, migration, and invasion. circ-ZDHHC5, rather than linear ZDHHC5 mRNA, rose in the tissues of patients with ESCC, plasma, and ESCC cell lines in comparison with normal controls. Knockdown of circ-ZDHHC5 inhibited tumorigenesis in ESCC cells, and the co-transfection of si-circ-ZDHHC5 and miR-217 mimics further enhanced the above effect. Noticeably, the present study showed that circ-ZDHHC5 was an miR-217 sponge that modulated the expression of zinc finger E-box binding homeobox 1 (ZEB1), further facilitating ESCC tumorigenesis. As revealed by this study, circ-ZDHHC5 can act as a new potential circular biomarker for detecting ESCC. It provides a novel perceptivity for the treatment of ESCC suggesting that circ-ZDHHC5 could impact on ESCC progression by sponging miR-217 with ZEB1. AU - Wang, Q. AU - Yang, L.* AU - Fan, Y.* AU - Tang, W.* AU - Sun, H.* AU - Xu, Z.* AU - Zhou, J.* AU - Zhang, Y.* AU - Zhu, B.* AU - Cao, X.* C1 - 60905 C2 - 49739 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Circ-ZDHHC5 accelerates esophageal squamous cell carcinoma progression in vitro via miR-217/ZEB1 axis. JO - Front. Cell Dev. Biol. VL - 8 PB - Frontiers Media Sa PY - 2020 SN - 2296-634X ER - TY - JOUR AB - Bone defect is a noteworthy health problem and is the second most transplanted tissue after blood. Numerous bone grafts are designed and applied in clinics. Limitations, however, from different aspects still exist, including limited supply, mechanical strength, and bioactivity. In this study, two biomimetic peptides (P2 and P6) are incorporated into a composite bioactive xeno hybrid bone graft named SmartBonePep®, with the aim to increase the bioactivity of the bone graft. The results, which include cytotoxicity, proliferation rate, confocal microscopy, gene expression, and protein qualification, successfully prove that the SmartBonePep® has multi-modal biological effects on human mesenchymal stem cells from bone marrow. The effective physical entrapment of P6 into a composite xeno-hybrid bone graft, withstanding manufacturing processes including exposure to strong organic solvents and ethylene oxide sterilization, increases the osteogenic potential of the stem cells as well as cell attachment and proliferation. P2 and P6 both show a strong biological potential and may be future candidates for enhancing the clinical performance of bone grafts. AU - Zhu, H.* AU - Blahnová, V.H.* AU - Perale,G.* AU - Xiao, J.* AU - Betge, F.* AU - Boniolo, F AU - Filová, E.* AU - Lyngstadaas, S.B.* AU - Haugen, H.J.* C1 - 60992 C2 - 49781 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Xeno-hybrid bone graft releasing biomimetic proteins promotes osteogenic differentiation of hMSCs. JO - Front. Cell Dev. Biol. VL - 8 PB - Frontiers Media Sa PY - 2020 SN - 2296-634X ER - TY - JOUR AB - In the past years, evidence has emerged that hallmarks of human metabolic disorders can be recapitulated in zebrafish using genetic, pharmacological or dietary interventions. An advantage of modeling metabolic diseases in zebrafish compared to other "lower organisms" is the presence of a vertebrate body plan providing the possibility to study the tissue-intrinsic processes preceding the loss of metabolic homeostasis. While the small size of zebrafish is advantageous in many aspects, it also has shortcomings such as the difficulty to obtain sufficient amounts for biochemical analyses in response to metabolic challenges. A workshop at the European Zebrafish Principal Investigator meeting in Trento, Italy, was dedicated to discuss the advantages and disadvantages of zebrafish to study metabolic disorders. This perspective article by the participants highlights strategies to achieve improved tissue-resolution for read-outs using "nano-sampling" approaches for metabolomics as well as live imaging of zebrafish expressing fluorescent reporter tools that inform on cellular or subcellular metabolic processes. We provide several examples, including the use of reporter tools to study the heterogeneity of pancreatic beta-cells within their tissue environment. While limitations exist, we believe that with the advent of new technologies and more labs developing methods that can be applied to minimal amounts of tissue or single cells, zebrafish will further increase their utility to study energy metabolism. AU - Dickmeis, T.* AU - Feng, Y.* AU - Mione, M.C.* AU - Ninov, N. AU - Santoro, M.* AU - Spaink, H.P.* AU - Gut, P.* C1 - 56114 C2 - 47194 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Nano-sampling and reporter tools to study metabolic regulation in zebrafish. JO - Front. Cell Dev. Biol. VL - 7 PB - Frontiers Media Sa PY - 2019 SN - 2296-634X ER - TY - JOUR AU - Fissore, R.A.* AU - Burton, A. AU - Lykke-Hartmann, K.* C1 - 55815 C2 - 46580 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Editorial: Molecular and cellular mechanisms in reproduction and early development. JO - Front. Cell Dev. Biol. VL - 7 PB - Frontiers Media Sa PY - 2019 SN - 2296-634X ER - TY - JOUR AB - A calorie-rich diet is one reason for the continuous spread of metabolic syndromes in western societies. Smart food design is one powerful tool to prevent metabolic stress, and the search for suitable bioactive additives is a continuous task. The nutrient-sensing insulin pathway is an evolutionary conserved mechanism that plays an important role in metabolism, growth and development. Recently, lipid cues capable to stimulate insulin signaling were identified. However, the mechanistic base of their activity remains obscure to date. We show that specific Akt/Protein-kinase B isoforms are responsive to different calorie-rich diets, and potentiate the activity of the cellular insulin cascade. Our data add a new dimension to existing models and position Drosophila as a powerful tool to study the relation between dietary lipid cues and the insulin-induced cellular signal pathway. AU - Trautenberg, L.C.* AU - Prince, E.* AU - Maas, C.* AU - Beier, N.* AU - Honold, F.* AU - Grzybek, M. AU - Brankatschk, M.* C1 - 57208 C2 - 47612 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland TI - Selective phosphorylation of Akt/Protein-kinase B isoforms in response to dietary cues. JO - Front. Cell Dev. Biol. VL - 7 PB - Frontiers Media Sa PY - 2019 SN - 2296-634X ER - TY - JOUR AU - Jiang, D. AU - Rinkevich, Y. C1 - 54681 C2 - 45759 CY - Avenue Du Tribunal Federal 34, Lausanne, Ch-1015, Switzerland SP - 133 TI - Defining skin fibroblastic cell types beyond CD90. JO - Front. Cell Dev. Biol. VL - 6 PB - Frontiers Media Sa PY - 2018 SN - 2296-634X ER - TY - JOUR AB - Immunotherapy is moving to the forefront of cancer treatments owing to impressive durable responses achieved with checkpoint blockade antibodies and adoptive T-cell therapy. Still, improvements are necessary since, overall, only a small percentage of patients benefit from current therapies. Here, I summarize evidence that DGK-α may represent an immunological checkpoint suppressing the activity of cytotoxic immunocytes in the tumor microenvironment. DGK-inhibitors can restore the antitumor function of tumor-suppressed adaptive and innate cytotoxic immunocytes. The activity of DGK-inhibitors lays downstream of current checkpoint blockade antibodies. Thus, synergistic effects are expected from combination strategies. Moreover, DGK-inhibitors may permit a double-strike attack on tumor cells as DGK-inhibition may not only re-instate immunological tumor attack but also may harm tumor cells directly by interfering with oncogenic survival pathways. Together, DGK-inhibitors have very promising characteristics and may be beneficially included into the armamentarium of cancer immunotherapeutics. AU - Nößner, E. C1 - 50751 C2 - 42636 TI - DGK-α: A checkpoint in cancer-mediated Immuno-inhibition and target for immunotherapy. JO - Front. Cell Dev. Biol. VL - 5 IS - MAR PY - 2017 SN - 2296-634X ER -