TY  - JOUR
AB  - Harsh environments enforce the expression of behavioural, morphological, physiological, and reproductive rejoinders, including torpor. Here we study the morphological, cellular, and molecular alterations in torpor architype in the colonial urochordate Botrylloides aff. leachii by employing whole organism Transmission electron (TEM) and light microscope observations, RNA sequencing, real-time polymerase chain reaction (qPCR) quantification of selected genes, and immunolocalization of WNT, SMAD and SOX2 gene expressions. On the morphological level, torpor starts with gradual regression of all zooids and buds which leaves the colony surviving as condensed vasculature remnants that may be 'aroused' to regenerate fully functional colonies upon changes in the environment. Simultaneously, we observed altered distributions of hemolymph cell types. Phagocytes doubled in number, while the number of morula cells declined by half. In addition, two new circulating cell types were observed, multi-nucleated and bacteria-bearing cells. RNA sequencing technology revealed marked differences in gene expression between different organism compartments and states: active zooids and ampullae, and between mid-torpor and naive colonies, or naive and torpid colonies. Gene Ontology term enrichment analyses further showed disparate biological processes. In torpid colonies, we observed overall 233 up regulated genes. These genes included NR4A2, EGR1, MUC5AC, HMCN2 and. Also, 27 transcription factors were upregulated in torpid colonies including ELK1, HDAC3, RBMX, MAZ, STAT1, STAT4 and STAT6. Interestingly, genes involved in developmental processes such as SPIRE1, RHOA, SOX11, WNT5A and SNX18 were also upregulated in torpid colonies. We further validated the dysregulation of 22 genes during torpor by utilizing qPCR. Immunohistochemistry of representative genes from three signaling pathways revealed high expression of these genes in circulated cells along torpor. WNT agonist administration resulted in early arousal from torpor in 80% of the torpid colonies while in active colonies WNT agonist triggered the torpor state. Abovementioned results thus connote unique transcriptome landscapes associated with Botrylloides leachii torpor.
AU  - Hyams, Y.*
AU  - Panov, J.*
AU  - Rosner, A.*
AU  - Brodsky, L.*
AU  - Rinkevich, Y.
AU  - Rinkevich, B.*
C1  - 65647
C2  - 52848
SP  - 22-36
TI  - Transcriptome landscapes that signify Botrylloides leachi (Ascidiacea) torpor states.
JO  - Dev. Biol.
VL  - 490
PY  - 2022
SN  - 0012-1606
ER  - 

TY  - JOUR
AB  - Malfunctions of motile cilia cause a variety of developmental defects and diseases in humans and animal model organisms. Defects include impaired mucociliary clearance of the airways, sperm immotility, hydrocephalus and organ laterality. Here, we characterize the evolutionary conserved Cfap43 gene by loss-of-function experiments in the mouse and the frog Xenopus laevis. Cfap43 is expressed in tissues carrying motile cilia and acts as a target gene of the transcription factor FOXJ1, which is essential for the induction of motile ciliogenesis. We show that CFAP43, a protein of unknown biochemical function, localizes to the ciliary axoneme. CFAP43 is involved in the regulation of the beating frequency of tracheal cilia and loss of CFAP43 causes severe mucus accumulation in the nasal cavity. Likewise, morphant and crispant frog embryos revealed impaired function of motile cilia of the larval epidermis, a model for airway mucociliary epithelia. CFAP43 participates in the formation of flagellar axonemes during spermatogenesis as mice mutant for Cfap43 display male infertility, consistent with observations in male sterile patients. In addition, mice mutant for Cfap43 display early onset hydrocephalus. Together, these results confirm the role of CFAP43 in the male reproductive tract and pinpoint additional functions in airway epithelia mucus clearance and brain development.
AU  - Rachev, E.*
AU  - Schuster-Gossler, K.*
AU  - Fuhl, F.*
AU  - Ott, T.*
AU  - Tveriakhina, L.*
AU  - Beckers, A.*
AU  - Hegermann, J.*
AU  - Boldt, K.*
AU  - Mai, M.*
AU  - Kremmer, E.
AU  - Ueffing, M.*
AU  - Blum, M.*
AU  - Gossler, A.*
C1  - 57796
C2  - 47916
CY  - 525 B St, Ste 1900, San Diego, Ca 92101-4495 Usa
SP  - 109-125
TI  - CFAP43 modulates ciliary beating in mouse and Xenopus.
JO  - Dev. Biol.
VL  - 459
IS  - 2
PB  - Academic Press Inc Elsevier Science
PY  - 2020
SN  - 0012-1606
ER  - 

TY  - JOUR
AB  - The enteric nervous system is thought to originate solely from the neural crest. Transgenic lineage tracing revealed a novel population of clonal pancreatic duodenal homeobox-1 (Pdx1)-Cre lineage progenitor cells in the tunica muscularis of the gut that produced pancreatic descendants as well as neurons upon differentiation in vitro. Additionally, an in vivo subpopulation of endoderm lineage enteric neurons, but not glial cells, was seen especially in the proximal gut. Analysis of early transgenic embryos revealed Pdx1-Cre progeny (as well as Sox-17-Cre and Foxa2-Cre progeny) migrating from the developing pancreas and duodenum at E11.5 and contributing to the enteric nervous system. These results show that the mammalian enteric nervous system arises from both the neural crest and the endoderm. Moreover, in adult mice there are separate Wnt1-Cre neural crest stem cells and Pdx1-Cre pancreatic progenitors within the muscle layer of the gut.
AU  - Brokhman, I.*
AU  - Xu, J.*
AU  - Coles, B.L.K.*
AU  - Razavi, R.*
AU  - Engert, S.
AU  - Lickert, H.
AU  - Babona-Pilipos, R.*
AU  - Morshead, C.M.*
AU  - Sibley, E.*
AU  - Chen, C.*
AU  - van der Kooy, D.*
C1  - 54794
C2  - 45854
SP  - 256-270
TI  - Dual embryonic origin of the mammalian enteric nervous system.
JO  - Dev. Biol.
VL  - 445
IS  - 2
PY  - 2019
SN  - 0012-1606
ER  - 

TY  - JOUR
AB  - Failure of neural tube closure leads to neural tube defects (NTDs), common congenital abnormalities in humans. Among the genes whose loss of function causes NTDs in mice, Grainyhead-like3 (Grhl3) is essential for spinal neural tube closure, with null mutants exhibiting fully penetrant spina bifida. During spinal neurulation Grhl3 is initially expressed in the surface (non-neural) ectoderm, subsequently in the neuroepithelial component of the neural folds and at the node-streak border, and finally in the hindgut endoderm. Here, we show that endoderm-specific knockout of Grhl3 causes late-arising spinal NTDs, preceded by increased ventral curvature of the caudal region which was shown previously to suppress closure of the spinal neural folds. This finding supports the hypothesis that diminished Grhl3 expression in the hindgut is the cause of spinal NTDs in the curly tail, carrying a hypomorphic Grhl3 allele. Complete loss of Grhl3 function produces a more severe phenotype in which closure fails earlier in neurulation, before the stage of onset of expression in the hindgut of wild-type embryos. This implicates additional tissues and NTD mechanisms in Grhl3 null embryos. Conditional knockout of Grhl3 in the neural plate and node-streak border has minimal effect on closure, suggesting that abnormal function of surface ectoderm, where Grhl3 transcripts are first detected, is primarily responsible for early failure of spinal neurulation in Grhl3 null embryos.
AU  - De Castro, S.C.P.*
AU  - Hirst, C.S.*
AU  - Savery, D.*
AU  - Rolo, A.P.*
AU  - Lickert, H.
AU  - Andersen, B.
AU  - Copp, A.J.*
AU  - Greene, N.D.E.*
C1  - 53363
C2  - 44706
CY  - San Diego
SP  - 130-137
TI  - Neural tube closure depends on expression of Grainyhead-like 3 in multiple tissues.
JO  - Dev. Biol.
VL  - 435
IS  - 2
PB  - Academic Press Inc Elsevier Science
PY  - 2018
SN  - 0012-1606
ER  - 

TY  - JOUR
AB  - The role of agrin, Lrp4 and MuSK, key organizers of neuromuscular synaptogenesis, in the developing CNS is only poorly understood. We investigated the role of these proteins in cultured mouse embryonic cortical neurons from wildtype and from Lrp4- and MuSK-deficient mice. Neurons from Lrp4-deficient mice had fewer but longer primary dendrites and a decreased density of puncta containing excitatory and inhibitory synapse-associated proteins. Neurons from MuSK-deficient mice had an altered dendritic branching pattern but no change in the density of puncta stained by antibodies against synapse-associated proteins. Transfection of TM-agrin compensated the dendritic branching deficits in Lrp4-deficient but not in MuSK-deficient neurons. TM-agrin transfection increased the density of excitatory synaptic puncta in MuSK-deficient but not in Lrp4-deficient mice and reduced the number of inhibitory synaptic puncta irrespective of MuSK and Lrp4 expression. Addition of purified soluble agrin to microisland cultures of cortical neurons revealed an Lrp4-dependent increase in the size and density of glutamatergic synaptic puncta and in mEPSC but not in mIPSC frequency and amplitude. Thus, agrin induced an Lrp4-independent increase in dendritic branch complexity, an Lrp4-dependent increase of excitatory synaptic puncta and an Lrp4- and MuSK-independent decrease in the density of puncta containing inhibitory synapse-associated proteins. These results establish selective roles for agrin, Lrp4 and MuSK during dendritogenesis and synaptogenesis in cultured CNS neurons.
AU  - Handara, G.
AU  - Hetsch, F.J.A.*
AU  - Jüttner, R.-R.*
AU  - Schick, A.*
AU  - Haupt, C.*
AU  - Rathjen, F.G.*
AU  - Kröger, S.*
C1  - 54638
C2  - 45738
SP  - 54-67
TI  - The role of agrin, Lrp4 and MuSK during dendritic arborization and synaptogenesis in cultured embryonic CNS neurons.
JO  - Dev. Biol.
VL  - 445
IS  - 1
PY  - 2018
SN  - 0012-1606
ER  - 

TY  - JOUR
AB  - During development of the CNS, stem and progenitor cell proliferation, cell fate designation, and patterning decisions are tightly regulated by interdependent networks of key transcriptional regulators. In a genetic approach we analyzed divergent functionality of the PAI and RED sub-domains of the Pax6 Paired domain (PD) during progenitor zone formation, motor and interneuron development, and peripheral connectivity at distinct levels within the neural tube: within the hindbrain, mutation of the PAI sub-domain severely affected patterning of the p3 and pMN domains and establishment of the corresponding motor neurons. Exit point designation of hypoglossal axons was disturbed in embryos harboring either mutations in the PD sub-domains or containing a functional Pax6 Null allele. At brachial spinal levels, we propose a selective involvement of the PAI sub-domain during patterning of ventral p2 and pMN domains, critically disturbing generation of specific motor neuron subtypes and increasing V2 interneuron numbers. Our findings present a novel aspect of how Pax6 not only utilizes its modular structure to perform distinct functions via its paired and homeodomain. Individual sub-domains can exert distinct functions, generating a new level of complexity for transcriptional regulation by one single transcription factor not only in dorso-ventral, but also rostro-caudal neural tube patterning.
AU  - Hüttl, R.E.
AU  - Eckstein, S.
AU  - Stahl, T.
AU  - Petricca, S.
AU  - Ninkovic, J.
AU  - Götz, M.
AU  - Huber, A.B.
C1  - 46377
C2  - 37556
CY  - San Diego
SP  - 86-103
TI  - Functional dissection of the Pax6 paired domain: Roles in neural tube patterning and peripheral nervous system development.
JO  - Dev. Biol.
VL  - 413
IS  - 1
PB  - Academic Press Inc Elsevier Science
PY  - 2016
SN  - 0012-1606
ER  - 

TY  - JOUR
AB  - The correct wiring of neuronal circuits is of crucial importance for the function of the vertebrate nervous system. Guidance cues like the neuropilin receptors (Npn) and their ligands, the semaphorins (Sema) provide a tight spatiotemporal control of sensory and motor axon growth and guidance. Among this family of guidance partners the Sema3A-Npn1 interaction has been shown to be of great importance, since defective signaling leads to wiring deficits and defasciculation. For the embryonic stage these defects have been well described, however, also after birth the organism can adapt to new challenges by compensational mechanisms. Therefore, we used the mouse lines Olig2-Cre;Npn1(cond) and Npn1(Sema-) to investigate how postnatal organisms cope with the loss of Npn1 selectively from motor neurons or a systemic dysfunctional Sema3A-Npn1 signaling in the entire organism, respectively. While in Olig2-Cre(+);Npn1(cond-/-) mice clear anatomical deficits in paw posturing, bone structure, as well as muscle and nerve composition became evident, Npn1(Sema-) mutants appeared anatomically normal. Furthermore, Olig2-Cre(+);Npn1(cond) mutants revealed a dysfunctional extensor muscle innervation after single-train stimulation of the N.radial. Interestingly, these mice did not show obvious deficits in voluntary locomotion, however, skilled motor function was affected. In contrast, Npn1(Sema-) mutants were less affected in all behavioral tests and able to improve their performance over time. Our data suggest that loss of Sema3A-Npn1 signaling is not the only cause for the observed deficits in Olig2-Cre(+);Npn1(cond-/-) mice and that additional, yet unknown binding partners for Npn1 may be involved that allow Npn1(Sema-) mutants to compensate for their developmental deficits.
AU  - Helmbrecht, M.S.
AU  - Soellner, H.
AU  - Truckenbrodt, A.M.
AU  - Sundermeier, J.
AU  - Cohrs, C.M.
AU  - Hans, W.
AU  - Hrabě de Angelis, M.
AU  - Feuchtinger, A.
AU  - Aichler, M.
AU  - Fouad, K.*
AU  - Huber, A.B.
C1  - 42985
C2  - 35914
CY  - San Diego
SP  - 2-14
TI  - Loss of Npn1 from motor neurons causes postnatal deficits independent from Sema3A signaling.
JO  - Dev. Biol.
VL  - 399
IS  - 1
PB  - Academic Press Inc Elsevier Science
PY  - 2015
SN  - 0012-1606
ER  - 

TY  - JOUR
AB  - The mammalian thalamus is an essential diencephalic derivative that plays unique roles in processing and relaying sensory and motor information to and from the cerebral cortex. The profile of transcription factors and lineage tracing experiments revealed a spatiotemporal relationship between diencephalic progenitor domains and discrete differentiated neurons contributing to thalamic nuclei. However, the precise molecular mechanisms by which heterogeneous thalamic neurons become specified and assemble into distinct thalamic nuclei are still poorly understood. Here, we show that a combinatorial interaction between the bHLH transcription factors Ascl1 and Helt is required for acquiring thalamic progenitor identity. Surprisingly, in the combined absence of Ascl1 and Helt, rostral thalamic progenitors (TH-R) adopt a molecular profile of a more rostral diencephalic derivative, the prethalamus. Furthermore, we show that the prethalamic factors Dlxs upregulated by Ascl1/. Helt deficiency play unique roles in regulating thalamic progenitor specification, and that derepression of Dlx2 and Dlx5 suppress generation of TH-R neurons. Taken together, our results suggest a model whereby the combined activity of two distinct bHLH factors plays a key role in the development of discrete classes of thalamic interneurons.
AU  - Song, H.*
AU  - Lee, B.*
AU  - Pyun, D.*
AU  - Guimera, J.
AU  - Son, Y.*
AU  - Yoon, J.*
AU  - Baek, K.*
AU  - Wurst, W.
AU  - Jeong, Y.*
C1  - 43019
C2  - 35945
CY  - San Diego
SP  - 280-291
TI  - Ascl1 and Helt act combinatorially to specify thalamic neuronal identity by repressing Dlxs activation.
JO  - Dev. Biol.
VL  - 398
IS  - 2
PB  - Academic Press Inc Elsevier Science
PY  - 2015
SN  - 0012-1606
ER  - 

TY  - JOUR
AB  - Motor neurons in the vertebrate spinal cord are stereotypically organized along the rostro-caudal axis in discrete columns that specifically innervate peripheral muscle domains. Originating from the same progenitor domain, the generation of spinal motor neurons is orchestrated by a spatially and temporally tightly regulated set of secreted molecules and transcription factors such as retinoic acid and the Lim homeodomain transcription factors Isl1 and Lhx1. However, the molecular interactions between these factors remained unclear. In this study we examined the role of the microRNA 9 (miR-9) in the specification of spinal motor neurons and identified Onecut1 (OC1) as one of its targets. miR-9 and OC1 are expressed in mutually exclusive patterns in the developing chick spinal cord, with high OC1 levels in early-born motor neurons and high miR-9 levels in late-born motor neurons. miR-9 efficiently represses OC1 expression in vitro and in vivo. Overexpression of miR-9 leads to an increase in late-born neurons, while miR-9 loss-of-function induces additional OC1(+) motor neurons that display a transcriptional profile typical of early-born neurons. These results demonstrate that regulation of OC1 by miR-9 is a crucial step in the specification of spinal motor neurons and support a model in which miR-9 expression in late-born LMCl neurons downregulates Isl1 expression through inhibition of OC1. In conclusion, our study contributes essential factors to the molecular network specifying spinal motor neurons and emphasizes the importance of microRNAs as key players in the generation of neuronal diversity.
AU  - Luxenhofer, G.
AU  - Helmbrecht, M.S.
AU  - Langhoff, J.
AU  - Giusti, S.A.*
AU  - Refojo, D.*
AU  - Huber, A.B.
C1  - 29159
C2  - 31226
CY  - San Diego
SP  - 358-370
TI  - MicroRNA-9 promotes the switch from early-born to late-born motor neuron populations by regulating Onecut transcription factor expression.
JO  - Dev. Biol.
VL  - 386
IS  - 2
PB  - Academic Press Inc Elsevier Science
PY  - 2014
SN  - 0012-1606
ER  - 

TY  - JOUR
AB  - Muscle spindles are complex stretch-sensitive mechanoreceptors. They consist of specialized skeletal muscle fibers, called intrafusal fibers, which are innervated in the central (equatorial) region by afferent sensory axons and in both polar regions by efferent γ-motoneurons. We show that AChRs are concentrated at the γ-motoneuron endplate as well as in the equatorial region where they colocalize with the sensory nerve ending. In addition to the AChRs, the contact site between sensory nerve ending and intrafusal muscle fiber contains a high concentration of choline acetyltransferase, vesicular acetylcholine transporter and the AChR-associated protein rapsyn. Moreover, bassoon, a component of the presynaptic cytomatrix involved in synaptic vesicle exocytosis, is present in γ-motoneuron endplates but also in the sensory nerve terminal. Finally, we demonstrate that during postnatal development of the γ-motoneuron endplate, the AChR subunit stoichiometry changes from the γ-subunit-containing fetal AChRs to the ε-subunit-containing adult AChRs, similar and approximately in parallel to the postnatal subunit maturation at the neuromuscular junction. In contrast, despite the onset of ε-subunit expression during postnatal development the γ-subunit remains detectable in the equatorial region by subunit-specific antibodies as well as by analysis of muscle spindles from mice with genetically-labeled AChR γ-subunits. These results demonstrate an unusual maturation of the AChR subunit composition at the annulospiral endings and suggest that in addition to the recently described glutamatergic secretory system, the sensory nerve terminals are also specialized for cholinergic synaptic transmission, synaptic vesicle storage and exocytosis.
AU  - Zhang, Y.
AU  - Wesolowski, M.*
AU  - Karakatsani, A.*
AU  - Witzemann, V.*
AU  - Kröger, S.*
C1  - 31849
C2  - 34812
CY  - San Diego
SP  - 227-235
TI  - Formation of cholinergic synapse-like specializations at developing murine muscle spindles.
JO  - Dev. Biol.
VL  - 393
IS  - 2
PB  - Academic Press Inc Elsevier Science
PY  - 2014
SN  - 0012-1606
ER  - 

TY  - JOUR
AB  - Understanding the molecular basis underlying the neurogenesis of mesencephalic-diencephalic Dopaminergic (mdDA) neurons is a major task fueled by their relevance in controlling locomotor activity and emotion and their involvement in neurodegenerative and psychiatric diseases. Increasing evidence suggests that mdDA neurons of the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) represent two main distinct neuronal populations, which, in turn, include specific neuronal subsets. Relevant studies provided important results on mdDA neurogenesis, but, nevertheless, have not yet clarified how the identity of mdDA neuronal subtypes is established and, in particular, whether neurogenic factors may direct progenitors towards the differentiation of specific mdDA neuronal subclasses. The transcription factor Otx2 is required for the neurogenesis of mesencephalic DA (mesDA) neurons and to control neuron subtype identity and sensitivity to the MPTP neurotoxin in the adult VTA. Here we studied whether Otx2 is required in mdDA progenitors for the generation of specific mdDA neuronal subtypes. We found that although expressed in virtually all mdDA progenitors, Otx2 is required selectively for the differentiation of VTA neuronal subtypes expressing Ahd2 and/or Calb but not for those co-expressing Girk2 and glyco-Dat. Moreover, mild over-expression of Otx2 in SNpc progenitors and neurons is sufficient to rescue En1 haploinsufficiency-dependent defects, such as progressive loss and increased MPTP sensitivity of SNpc neurons. Collectively, these data suggest that mdDA progenitors exhibit differential sensitivity to Otx2, which selectively influences the generation of a large and specific subset of VTA neurons. In addition, these data suggest that Otx2 and En1 may share similar properties and control survival and vulnerability to MPTP neurotoxin respectively in VTA and SNpc.
AU  - di Giovannantonio, L.G.*
AU  - di Salvio, M.*
AU  - Acampora, D.*
AU  - Prakash, N.
AU  - Wurst, W.
AU  - Simeone, A.*
C1  - 11174
C2  - 30534
SP  - 176-183
TI  - Otx2 selectively controls the neurogenesis of specific neuronal subtypes of the ventral tegmental area and compensates En1-dependent neuronal loss and MPTP vulnerability.
JO  - Dev. Biol.
VL  - 373
IS  - 1
PB  - Elsevier Academic Press
PY  - 2013
SN  - 0012-1606
ER  - 

TY  - JOUR
AB  - The balanced proliferation and cell cycle exit of neural progenitors, by generating the appropriate amount of postmitotic progeny at the correct time and in the proper location, is required for the establishment of the highly ordered structure of the adult brain. Little is known about the extrinsic signals regulating these processes, particularly in the midbrain. Fibroblast growth factor (Fgf) 15, the mouse ortholog of FGF19 and member of an atypical Fgf subfamily, is prominently expressed in the dorsolateral midbrain of the midgestational mouse embryo. In the absence of Fgf15, dorsal midbrain neural progenitors fail to exit the cell cycle and to generate the proper amount of postmitotic neurons. We show here that this is due to the altered expression of inhibitory/neurogenic and proneural/neuronal differentiation helix-loop-helix transcription factor (TF) genes. The expression of Id1, Id3, and Hes5 was strongly increased and ectopically expanded, whereas the expression of Ascl1 (Mash1), Neurog1 (Ngn1) and Neurog2 (Ngn2) was strongly decreased and transcription of Neurod1 (NeuroD) was completely abolished in the dorsolateral midbrain of Fgf15(-/-) mice. These abnormalities were not caused by the mis-expression of cell cycle regulatory proteins such as cyclin-dependent kinase inhibitors or retinoblastoma proteins. Furthermore, human FGF19 promotes cell cycle exit of murine dorsal neural progenitors in vitro. Therefore, our data suggest that Fgf15 is a crucial signaling molecule regulating the postmitotic transition of dorsal neural progenitors and thus the initiation and proper progression of dorsal midbrain neurogenesis in the mouse, by controlling the expression of neurogenic and proneural TFs.
AU  - Fischer, T.
AU  - Faus-Kessler, T.
AU  - Welzl, G.
AU  - Simeone, A.*
AU  - Wurst, W.
AU  - Prakash, N.
C1  - 5936
C2  - 28414
CY  - San Diego, CA
SP  - 496-510
TI  - Fgf15-mediated control of neurogenic and proneural gene expression regulates dorsal midbrain neurogenesis.
JO  - Dev. Biol.
VL  - 350
IS  - 2
PB  - Elsevier
PY  - 2011
SN  - 0012-1606
ER  - 

TY  - JOUR
AB  - Interaction of the axon guidance receptor Neuropilin-1 (Npn-1) with its repulsive ligand Semaphorin 3A (Sema3A) is crucial for guidance decisions, fasciculation, timing of growth and axon-axon interactions of sensory and motor projections in the embryonic limb. At cranial levels, Npn-1 is expressed in motor neurons and sensory ganglia and loss of Sema3A-Npn-1 signaling leads to defasciculation of the superficial projections to the head and neck. The molecular mechanisms that govern the initial fasciculation and growth of the purely motor projections of the hypoglossal and abducens nerves in general, and the role of Npn-1 during these events in particular are, however, not well understood. We show here that selective removal of Npn-1 from somatic motor neurons impairs initial fasciculation and assembly of hypoglossal rootlets and leads to reduced numbers of abducens and hypoglossal fibers. Ablation of Npn-1 specifically from cranial neural crest and placodally derived sensory tissues recapitulates the distal defasciculation of mixed sensory-motor nerves of trigeminal, facial, glossopharyngeal and vagal projections, which was observed in Npn-1(-/-) and Npn-1(Sema-) mutants. Surprisingly, the assembly and fasciculation of the purely motor hypoglossal nerve are also impaired and the number of Schwann cells migrating along the defasciculated axonal projections is reduced. These findings are corroborated by partial genetic elimination of cranial neural crest and embryonic placodes, where loss of Schwann cell precursors leads to aberrant growth patterns of the hypoglossal nerve. Interestingly, rostral turning of hypoglossal axons is not perturbed in any of the investigated genotypes. Thus, initial hypoglossal nerve assembly and fasciculation, but not later guidance decisions depend on Npn-1 expression and axon-Schwann cell interactions.
AU  - Hüttl, R.E.
AU  - Huber, A.B.
C1  - 6576
C2  - 28930
SP  - 230-241
TI  - Cranial nerve fasciculation and Schwann cell migration are impaired after loss of Npn-1.
JO  - Dev. Biol.
VL  - 359
IS  - 2
PB  - Elsevier
PY  - 2011
SN  - 0012-1606
ER  - 

TY  - JOUR
AB  - Fibroblast growth factor (FGF) signalling has important roles in the development of the embryonic pharyngeal (branchial) arches, but its effects on innervation of the arches and associated structures have not been studied extensively. We investigated the consequences of deleting two receptor tyrosine kinase (RTK) antagonists of the Sprouty (Spry) gene family on the early development of the branchial nerves. The morphology of the facial, glossopharyngeal and vagus nerves are abnormal in Spry1-/-;Spry2-/- embryos. We identify specific defects in the epibranchial placodes and neural crest, which contribute sensory neurons and glia to these nerves. A dissection of the tissue-specific roles of these genes in branchial nerve development shows that Sprouty gene deletion in the pharyngeal epithelia can affect both placode formation and neural crest fate. However, epithelial-specific gene deletion only results in defects in the facial nerve and not the glossopharyngeal and vagus nerves, suggesting that the facial nerve is most sensitive to perturbations in RTK signalling. Reducing the Fgf8 gene dosage only partially rescued defects in the glossopharyngeal nerve and was not sufficient to rescue facial nerve defects, suggesting that FGF8 is functionally redundant with other RTK ligands during facial nerve development.
AU  - Simrick, S.*
AU  - Lickert, H.
AU  - Basson, M.A.*
C1  - 6503
C2  - 28821
SP  - 147-155
TI  - Sprouty genes are essential for the normal development of epibranchial ganglia in the mouse embryo.
JO  - Dev. Biol.
VL  - 358
IS  - 1
PB  - Elsevier
PY  - 2011
SN  - 0012-1606
ER  - 

TY  - JOUR
AB  - Large-scale mouse mutagenesis initiatives have provided new mouse mutants that are useful models of human deafness and vestibular dysfunction. Catweasel is a novel N-ethyl-N-nitrosourea (ENU)-induced Mutation. Heterozygous catweasel mutant mice exhibit mild headtossing associated with a posterior crista defect. We mapped the catweasel mutation to a critical region of 13 Mb on chromosome 12 containing the Six1, -4 and -6 genes. We identified a basepair substitution in exon I of the Six1 gene that changes a conserved glutamic acid (E) at position 121 to a glycine (G) in the Six1 homeodomain. Cwe/Cwe animals lack Preyer and righting reflexes, display severe headshaking and have severely truncated cochlea and semicircular canals. Cwe/Cwe animals had very few hair cells in the utricle, but their ampullae and cochlea were devoid of any hair cells. Bmp4, Jag1 and Sox2 expression were largely absent at early stages of sensory development and NeuroD expression was reduced in the developing vestibulo-acoustic ganglion. Lastly we show that Six1 genetically interacts with Jag1. We propose that the catweasel phenotype is due to a hypomorphic mutation in Six1 and that catweasel mice are a Suitable model for branchio-oto-renal syndrome. In addition Six1 has a pivotal role in early sensory patch development and may act in the same genetic pathway as Jag1.
AU  - Bosman, E.A.*
AU  - Quint, E.*
AU  - Fuchs, H.
AU  - Hrabě de Angelis, M.
AU  - Steel, K.P.*
C1  - 913
C2  - 26159
SP  - 285-296
TI  - Catweasel mice: A novel role for Six1 in sensory patch development and a model for branchio-oto-renal syndrome.
JO  - Dev. Biol.
VL  - 328
IS  - 2
PB  - Elsevier
PY  - 2009
SN  - 0012-1606
ER  - 

TY  - JOUR
AB  - The upper rhombic lip, a prominent germinal zone of the cerebellum, was recently demonstrated to generate different neuronal cell types over time from spatial subdomains. We have characterized the differentiation of the upper rhombic lip derived granule cell population in stable GFP-transgenic zebrafish in the context of zebrafish cerebellar morphogenesis. Time-lapse analysis followed by individual granule cell tracing demonstrates that the zebrafish upper rhombic lip is spatially patterned along its mediolateral axis producing different granule cell populations simultaneously. Time-lapse recordings of parallel fiber projections and retrograde labeling reveal that spatial patterning within the rhombic lip corresponds to granule cells of two different functional compartments of the mature cerebellum: the eminentia granularis and the corpus cerebelli. These cerebellar compartments in teleosts correspond to the mammalian vestibulocerebellar and non-vestibulocerebellar system serving balance and locomotion control, respectively. Given the high conservation of cerebellar development in vertebrates, spatial partitioning of the mammalian granule cell population and their corresponding earlier-produced deep nuclei by patterning within the rhombic lip may also delineate distinct functional compartments of the cerebellum. Thus, our findings offer an explanation for how specific functional cerebellar circuitries are laid down by spatio-temporal patterning of cerebellar germinal zones during early brain development.
AU  - Volkmann, K.
AU  - Rieger, S.
AU  - Babaryka, A.N.
AU  - Köster, R.W.
C1  - 688
C2  - 25110
SP  - 167-180
TI  - The zebrafish cerebellar rhombic lip is spatially patterned in producing granule cell populations of different functional compartments.
JO  - Dev. Biol.
VL  - 313
IS  - 1
PB  - Elsevier
PY  - 2008
SN  - 0012-1606
ER  - 

TY  - JOUR
AB  - The mid-/hindbrain organizer (MHO) is characterized by the expression of a network of genes, which controls the patterning and development of the prospective midbrain and anterior hindbrain. One key molecule acting at the MHO is the fibroblast growth factor (Fgf) 8. Ectopic expression of Fgf8 induces genes that are normally expressed at the mid-/hindbrain boundary followed by the induction of midbrain and anterior hindbrain structures. Inactivation of the Fgf receptor (Fgfr) 1 gene, which was thought to be the primary transducer of the Fgf8 signal at the MHO, in the mid-/hindbrain region, leads to a deletion of dorsal structures of the mid-/hindbrain region, whereas ventral tissues are less severely affected. This suggests that other Fgfrs might be responsible for ventral mid-/hindbrain region development. Here we report the analysis of Fgfr2 conditional knockout mice, lacking the Fgfr2 in the mid-/hindbrain region and of Fgfr3 knockout mice with respect to the mid-/hindbrain region. In both homozygous mouse mutants, patterning of the mid-/hindbrain region is not altered, neuronal populations develop normal and are maintained into adulthood. This analysis shows that the Fgfr2 and the Fgfr3 on their own are dispensable for the development of the mid-/hindbrain region. We suggest functional redundancy of Fgf receptors in the mid-/hindbrain region.
AU  - Blak, A.A.
AU  - Naserke, T.
AU  - Saarimäki-Vire, J.*
AU  - Peltopuro, P.*
AU  - Giraldo-Velasquez, M.*
AU  - Vogt Weisenhorn, D.M.
AU  - Prakash, N.
AU  - Sendtner, M.*
AU  - Partanen, J.*
AU  - Wurst, W.
C1  - 4683
C2  - 24355
SP  - 231-243
TI  - Fgfr2 and Fgfr3 are not required for patterning and maintenance of the midbrain and anterior hindbrain.
JO  - Dev. Biol.
VL  - 303
PB  - Elsevier
PY  - 2007
SN  - 0012-1606
ER  - 

TY  - JOUR
AB  - Our understanding of the cellular and molecular mechanisms underlying the adult neural stem cell state remains fragmentary. To provide new models on this issue, we searched for stem cells in the adult brain of the zebrafish. Using BrdU tracing and immunodetection of cell-type-specific markers, we demonstrate that the adult zebrafish telencephalon contains self-renewing progenitors, which show features of adult mammalian neural stem cells but distribute along the entire dorso-ventral extent of the telencephalic ventricular zone. These progenitors give rise to newborn neurons settling close to the ventricular zone within the telencephalon proper. They have no equivalent in mammals and therefore constitute a new model of adult telencephalic neural stem cells. In addition, progenitors from the ventral subpallium generate rapidly dividing progenitors and neuroblasts that reach the olfactory bulb (OB) via a rostral migratory stream and differentiate into GABAergic and TH-positive neurons. These ventral progenitors are comparable to the mammalian neural stem cells of the subependymal zone. Interestingly, dorsal and ventral progenitors in the adult telencephalon express a different combination of transcription factors than their embryonic counterparts. In the case of neurogenin1, this is due to the usage of different enhancer elements. Together, our results highlight the conserved and unique phylogenic and ontogenic features of adult neurogenesis in the zebrafish telencephalon and open the way to the identification of adult neural stem cell characters in cross-species comparative studies. © 2006 Elsevier Inc. All rights reserved.
AU  - Adolf, B.
AU  - Chapouton, P.
AU  - Lam, C.S.*
AU  - Topp, S.
AU  - Tannhäuser, B.
AU  - Strähle, U.*
AU  - Götz, M.
AU  - Bally-Cuif, L.
C1  - 5244
C2  - 23871
SP  - 278-293
TI  - Conserved and acquired features of adult neurogenesis in the zebrafish telencephalon.
JO  - Dev. Biol.
VL  - 295
IS  - 1
PY  - 2006
SN  - 0012-1606
ER  - 

TY  - JOUR
AU  - Hamade, A.*
AU  - Begemann, G.*
AU  - Bally-Cuif, L.
AU  - Genêt, C.*
AU  - Sabatier, F.*
AU  - Bonnieu, A.*
AU  - Cousin, X.*
C1  - 1520
C2  - 23149
SP  - 127-140
TI  - Retinoic acid activates myogenesis in vivo through Fgf8 signalling.
JO  - Dev. Biol.
VL  - 289
PY  - 2006
SN  - 0012-1606
ER  - 

TY  - JOUR
AU  - Jukkola, T.*
AU  - Lahti, L.*
AU  - Naserke, T.
AU  - Wurst, W.
AU  - Partanen, J.*
C1  - 3168
C2  - 23953
SP  - 141-157
TI  - FGF regulated gene-expression and neuronal differentiation in the developing midbrain-hindbrain region.
JO  - Dev. Biol.
VL  - 297
PY  - 2006
SN  - 0012-1606
ER  - 

TY  - JOUR
AB  - The transcription factors Emx1 and Emx2 exert important functions during development of the cerebral cortex, including its arealization. Here, we addressed their role in development of the derivatives of the midline region in the telencephalon. The center of the midline region differentiates into the choroid plexus, but little is known about its molecular specification. As we noted a lack of Emx1 or 2 expression in the midline region early in development, we interfered by misexpressing Emx1 and/or Emx2 in this region of the chick telencephalon. Ectopic expression of either Emx1 or Emx2 prior to HH 13 instructed a neuroepithelial identity in the previous midline region instead of a choroidal fate. Thus, Gli3 and Lhx2 normally restricted to the neuroepithelium expanded into the Emx misexpressing region. This was accompanied by down-regulation of Otx2 and BMP7, which implicates that these factors are essential for choroid plexus specification and differentiation. Interestingly, the region next to the ectopic Emx-misexpression then acquired a hybrid identity with some choroidal features such as Bmp7, Otx2 and Ttr gene expression, as well as some neuroepithelial features. These observations indicate that the expression levels of Emx1 and/or Emx2 restrict the prospective choroid plexus territory, a novel role of these transcription factors.
AU  - von Frowein, J.
AU  - Wizenmann, A.
AU  - Götz, M.
C1  - 4441
C2  - 24131
SP  - 239-252
TI  - The transcription factors Emx1 and Emx2 suppress choroid plexus development and promote neuroepithelial cell fate.
JO  - Dev. Biol.
VL  - 296
IS  - 1
PY  - 2006
SN  - 0012-1606
ER  - 

TY  - JOUR
AB  - Signaling molecules regulating development of the midbrain and anterior hindbrain are expressed in distinct bands of cells around the midbrain–hindbrain boundary. Very little is known about the mechanisms responsible for the coherence of this signaling center. One of the fibroblast growth factor (FGF) receptors, Fgfr1, is required for establishment of a straight border between developing mid- and hindbrain. Here we show that the cells close to the border have unique features. Unlike the cells further away, these cells express Fgfr1 but not the other FGF receptors. The cells next to the midbrain–hindbrain boundary express distinct cell cycle regulators and proliferate less rapidly than the surrounding cells. In Fgfr1 mutants, these cells fail to form a coherent band at the boundary. The slowly proliferating boundary cells are necessary for development of the characteristic isthmic constriction. They may also contribute to compartmentalization of this brain region.
AU  - Trokovic, R.*
AU  - Jukkola, T.*
AU  - Saarimaki, J.*
AU  - Peltopuro, P.*
AU  - Naserke, T.*
AU  - Weisenhorn, D.M.
AU  - Trokovic, N.*
AU  - Wurst, W.
AU  - Partanen, J.*
C1  - 2506
C2  - 22738
SP  - 428-439
TI  - Fgfr1-dependent boundary cells between developing mid- and hindbrain.
JO  - Dev. Biol.
VL  - 278
IS  - 2
PY  - 2005
SN  - 0012-1606
ER  - 

TY  - JOUR
AB  - Vertebrate somitogenesis comprises the generation of a temporal periodicity, the establishment of anteroposterior compartment identity, and the translation of the temporal periodicity into the metameric pattern of somites. Molecular players at each of these steps are beginning to be identified. Especially, members of the Notch signaling cascade appear to be involved in setting up the somitogenesis clock and subsequent events. We had previously demonstrated specific expression of the mHey1 and mHey2 basic helix-loop-helix (bHLH) factors during somitogenesis. Here we show that perturbed Notch signaling in Dll1 and Notch1 knockout mutants affects this expression in the presomitic mesoderm (PSM) and the somites. In the caudal PSM, however, mHey2 expression is maintained and thus is likely to be independent of Notch signaling. Furthermore, we analysed the dynamic expression of the respective chicken c-Hey1 and c-Hey2 genes during somitogenesis. Not only is c-Hey2 rhythmically expressed across the chicken presomitic mesoderm like c-hairy1, but its transcription is similarly independent of de novo protein synthesis. In contrast, the dynamic expression of c-Hey1 is restricted to the anterior segmental plate. Both c-Hey genes are coexpressed with c-hairy1 in the posterior somite half. Further in vitro and in vivo interaction assays demonstrated direct homo- and heterodimerisation between these hairy-related bHLH proteins, suggesting a combinatorial action in both the generation of a temporal periodicity and the anterior–posterior somite compartmentalisation.
AU  - Leimeister, C.*
AU  - Dale, K.*
AU  - Fischer, A.*
AU  - Klamt, B.*
AU  - Hrabě de Angelis, M.
AU  - Radtke, F.*
AU  - McGrew, M.J.*
AU  - Pourquie, O.*
AU  - Gessler, M.*
C1  - 22307
C2  - 21113
SP  - 91-103
TI  - Oscillating Expression of c-Hey2 in the Presomitic Mesoderm Suggests That the Segmentation Clock May Use Combinatorial Signaling through Multiple Interacting bHLH Factors.
JO  - Dev. Biol.
VL  - 227
IS  - 1
PY  - 2000
SN  - 0012-1606
ER  - 

TY  - JOUR
AB  - Genes of theHoxDcomplex have a crucial role in the morphogenesis of vertebrate limbs. During development, their functional domains are colinear with their genomic positions within theHoxDcluster such thatHoxd13andHoxd12are necessary for digit development, whereasHoxd11andHoxd10are involved in making forearms. Mutational analyses of these genes have demonstrated their importance and illustrated the requirement for a precise control of their expression during early limb morphogenesis. To study the nature of this control, we have scanned the posterior part of theHoxDcomplex with a targeted reporter transgene and analyzed the response of this foreign promoter to limb regulatory influences. The results suggest that this regulation is achieved through the opposite effects of two enhancer elements which would compete with each other for interacting with nearby-located promoters. The physical position of a given gene within this genomic interval of opposite regulations might thus determine its final expression pattern. This model provides a conceptual link between the morphology of the future limb and the genetic organization of theHoxgene cluster, a translation of a genomic context into a morphogenetic topology.
AU  - Herault, Y.*
AU  - Beckers, J.
AU  - Gerard, M.*
AU  - Duboule, D.*
C1  - 22305
C2  - 21111
SP  - 157-165
TI  - Hox Gene Expression in Limbs : Colinearity by Opposite Regulatory Controls.
JO  - Dev. Biol.
VL  - 208
IS  - 1
PY  - 1999
SN  - 0012-1606
ER  -