TY  - JOUR
AB  - Background: MiR-9 is a small non-coding RNA that is highly conserved between species and primarily expressed in the central nervous system (CNS). It is known to influence proliferation and neuronal differentiation in the brain and spinal cord of different vertebrates. Different studies have pointed to regional and species-specific differences in the response of neural progenitors to miR-9. Methods: In ovo and ex ovo electroporation was used to overexpress or reduce miR-9 followed by mRNA in situ hybridisation and immunofluorescent stainings to evaluate miR-expression and the effect of changed miR-9 expression. Results: We have investigated the expression and function of miR-9 during early development of the mid-hind-brain region (MH) in chick. Our analysis reveals a closer relationship of chick miR-9 to mammalian miR-9 than to fish and a dynamic expression pattern in the chick neural tube. Early in development, miR-9 is diffusely expressed in the entire brain, bar the forebrain, and it becomes more restricted to specific areas of the CNS at later stages. MiR-9 overexpression at HH9-10 results in a reduction of FGF8 expression and premature neuronal differentiation in the mid-hindbrain boundary (MHB). Within the midbrain miR-9 does not cause premature neuronal differentiation it rather reduces proliferation in the midbrain. Conclusion: Our findings indicate that miR-9 has regional specific effects in the developing mid-hindbrain region with a divergence of response of regional progenitors.
AU  - Alwin Prem Anand, A.*
AU  - Huber, C.*
AU  - Asnet Mary, J.*
AU  - Gallus, N.*
AU  - Leucht, C.
AU  - Klafke, R.
AU  - Hirt, B.*
AU  - Wizenmann, A.*
C1  - 53046
C2  - 44468
CY  - London
TI  - Expression and function of microRNA-9 in the mid-hindbrain area of embryonic chick.
JO  - BMC Dev. Biol.
VL  - 18
IS  - 1
PB  - Biomed Central Ltd
PY  - 2018
ER  - 

TY  - JOUR
AB  - BACKGROUND: During early stages of brain development, secreted molecules, components of intracellular signaling pathways and transcriptional regulators act in positive and negative feed-back or feed-forward loops at the mid-hindbrain boundary. These genetic interactions are of central importance for the specification and subsequent development of the adjacent mid- and hindbrain. Much less, however, is known about the regulatory relationship and functional interaction of molecules that are expressed in the tectal anlage after tectal fate specification has taken place and tectal development has commenced. RESULTS: Here, we provide experimental evidence for reciprocal regulation and subsequent cooperation of the paired-type transcription factors Pax3, Pax7 and the TALE-homeodomain protein Meis2 in the tectal anlage. Using in ovo electroporation of the mesencephalic vesicle of chick embryos we show that (i) Pax3 and Pax7 mutually regulate each other's expression in the mesencephalic vesicle, (ii) Meis2 acts downstream of Pax3/7 and requires balanced expression levels of both proteins, and (iii) Meis2 physically interacts with Pax3 and Pax7. These results extend our previous observation that Meis2 cooperates with Otx2 in tectal development to include Pax3 and Pax7 as Meis2 interacting proteins in the tectal anlage. CONCLUSION: The results described here suggest a model in which interdependent regulatory loops involving Pax3 and Pax7 in the dorsal mesencephalic vesicle modulate Meis2 expression. Physical interaction with Meis2 may then confer tectal specificity to a wide range of otherwise broadly expressed transcriptional regulators, including Otx2, Pax3 and Pax7.
AU  - Agoston, Z.*
AU  - Li, N.*
AU  - Haslinger, A.
AU  - Wizenmann, A.*
AU  - Schulte, D.*
C1  - 7484
C2  - 29744
TI  - Genetic and physical interaction of Meis2, Pax3 and Pax7 during dorsal midbrain development.
JO  - BMC Dev. Biol.
VL  - 12
PB  - BioMed Central
PY  - 2012
ER  - 

TY  - JOUR
AB  - BACKGROUND: Neurogenesis control and the prevention of premature differentiation in the vertebrate embryo are crucial processes, allowing the formation of late-born cell types and ensuring the correct shape and cytoarchitecture of the brain. Members of the Hairy/Enhancer of Split (Hairy/E(spl)) family of bHLH-Orange transcription factors, such as zebrafish Her3, 5, 9 and 11, are implicated in the local inhibition of neurogenesis to maintain progenitor pools within the early neural plate. To better understand how these factors exert their inhibitory function, we aimed to isolate some of their functional interactors. RESULTS: We used a yeast two-hybrid screen with Her5 as bait and recovered a novel zebrafish Hairy/E(spl) factor - Her8a. Using phylogenetic and synteny analyses, we demonstrate that her8a evolved from an ancient duplicate of Hes6 that was recently lost in the mammalian lineage. We show that her8a is expressed across the mid- and anterior hindbrain from the start of segmentation. Through knockdown and misexpression experiments, we demonstrate that Her8a is a negative regulator of neurogenesis and plays an essential role in generating progenitor pools within rhombomeres 2 and 4 - a role resembling that of Her3. Her8a co-purifies with Her3, suggesting that Her8a-Her3 heterodimers may be relevant in this domain of the neural plate, where both proteins are co-expressed. Finally, we demonstrate that her8a expression is independent of Notch signaling at the early neural plate stage but that SoxB factors play a role in its expression, linking patterning information to neurogenesis control. Overall, the regulation and function of Her8a differ strikingly from those of its closest relative in other vertebrates - the Hes6-like proteins. CONCLUSIONS: Our results characterize the phylogeny, expression and functional interactions involving a new Her factor, Her8a, and highlight the complex interplay of E(spl) proteins that generates the neurogenesis pattern of the zebrafish early neural plate.
AU  - Webb, K.J.
AU  - Coolen, M.
AU  - Gloeckner, C.J.
AU  - Stigloher, C.
AU  - Bahn, B.
AU  - Topp, S.
AU  - Ueffing, M.
AU  - Bally-Cuif, L.
C1  - 5268
C2  - 28640
TI  - The Enhancer of split transcription factor Her8a is a novel dimerisation partner for Her3 that controls anterior hindbrain neurogenesis in zebrafish.
JO  - BMC Dev. Biol.
VL  - 11
PB  - Biomed Central Ltd
PY  - 2011
ER  - 

TY  - JOUR
AB  - BACKGROUND: The transcription factor Pax6 functions in the specification and maintenance of the differentiated cell lineages in the endocrine pancreas. It has two DNA binding domains, the paired domain and the homeodomain, in addition to a C-terminal transactivation domain. The phenotype of Pax6-/- knockout mice suggests non-redundant functions of the transcription factor in the development of glucagon-expressing alpha-cells as this cell type is absent in the mutants. We ask the question of how the differentiation of pancreatic endocrine cells, in particular that of alpha-cells, is affected by selective inactivation of either one of the three major domains of Pax6. RESULTS: The Pax6Aey18 mutant mouse line, in which the paired domain is inactivated, showed a phenotype similar to that of Pax6-/- knockout mice with a near complete absence of glucagon-positive alpha-cells (0-4 cells/section; < or =1% of wt), reduced beta-cell area (74% of wt) and disorganized islets. The proportion of ghrelin-positive epsilon-cells was expanded. In Pax6Sey-Neu mutants, which lack the transactivation domain, alpha-and beta-cells where reduced to 25 and 40% of wt, respectively. We also studied two mouse lines with mutations in the homeodomain, Pax64Neu and Pax6132-14Neu. Neighboring amino acids are affected in the two lines and both point mutations abolish DNA binding of the classical P3 homeodomain target sequence. The pancreatic phenotype of the two mutants however was divergent. While Pax64Neu homozygotes showed a reduction of alpha- and beta-cells to 59 and 61%, respectively, pancreatic endocrine development was unaltered in the Pax6132-14Neu mutant strain. CONCLUSIONS: We show that inactivation of the Pax6 paired domain leads to a more severe phenotype with regards to the differentiation of pancreatic alpha-cells than the loss of the transactivation domain. The analysis of two different homeodomain mutants suggests that the binding of Pax6 to P3 homeodomain consensus sequences is not required for alpha-cell development. It rather seems that the homeodomain has a modulating role in Pax6 function, possibly by facilitating a PH0-like binding confirmation on paired domain target genes like proglucagon. This function is differentially affected by the two homeodomain mutations analyzed in this study.
AU  - Dames, P.*
AU  - Puff, R.*
AU  - Weise, M.*
AU  - Parhofer, K.G.*
AU  - Göke, B.*
AU  - Götz, M.
AU  - Graw, J.
AU  - Favor, J.
AU  - Lechner, A.*
C1  - 1999
C2  - 27510
TI  - Relative roles of the different Pax6 domains for pancreatic alpha cell development.
JO  - BMC Dev. Biol.
VL  - 10
PB  - BioMed Central Ltd.
PY  - 2010
ER  - 

TY  - JOUR
AB  - BACKGROUND: In Drosophila, mutations in the gene eyes absent (eya) lead to severe defects in eye development. The functions of its mammalian orthologs Eya1-4 are only partially understood and no mouse model exists for Eya3. Therefore, we characterized the phenotype of a new Eya3 knockout mouse mutant. RESULTS: Expression analysis of Eya3 by in-situ hybridizations and beta-Gal-staining of Eya3 mutant mice revealed abundant expression of the gene throughout development, e.g. in brain, eyes, heart, somites and limbs suggesting pleiotropic effects of the mutated gene. A similar complex expression pattern was observed also in zebrafish embryos. The phenotype of young adult Eya3 mouse mutants was systematically analyzed within the German Mouse Clinic. There was no obvious defect in the eyes, ears and kidneys of Eya3 mutant mice. Homozygous mutants displayed decreased bone mineral content and shorter body length. In the lung, the tidal volume at rest was decreased, and electrocardiography showed increased JT- and PQ intervals as well as decreased QRS amplitude. Behavioral analysis of the mutants demonstrated a mild increase in exploratory behavior, but decreased locomotor activity and reduced muscle strength. Analysis of differential gene expression revealed 110 regulated genes in heart and brain. Using real-time PCR, we confirmed Nup155 being down regulated in both organs. CONCLUSION: The loss of Eya3 in the mouse has no apparent effect on eye development. The wide-spread expression of Eya3 in mouse and zebrafish embryos is in contrast to the restricted expression pattern in Xenopus embryos. The loss of Eya3 in mice leads to a broad spectrum of minor physiological changes. Among them, the mutant mice move less than the wild-type mice and, together with the effects on respiratory, muscle and heart function, the mutation might lead to more severe effects when the mice become older. Therefore, future investigations of Eya3 function should focus on aging mice.
AU  - Söker, T.
AU  - Dalke, C.
AU  - Puk, O.
AU  - Floß, T.
AU  - Becker, L.
AU  - Bolle, I.
AU  - Favor, J.
AU  - Hans, W.
AU  - Hölter, S.M.
AU  - Horsch, M.
AU  - Kallnik, M.
AU  - Kling, E.
AU  - Mörth, C.
AU  - Schrewe, A.
AU  - Stigloher, C.
AU  - Topp, S.
AU  - Gailus-Durner, V.
AU  - Naton, B.
AU  - Beckers, J.
AU  - Fuchs, H.
AU  - Ivandic, B.*
AU  - Klopstock, T.*
AU  - Schulz, S.*
AU  - Wolf, E.*
AU  - Wurst, W.
AU  - Bally-Cuif, L.
AU  - Hrabě de Angelis, M.
AU  - Graw, J.
C1  - 2384
C2  - 25889
TI  - Pleiotropic effects in Eya3 knockout mice.
JO  - BMC Dev. Biol.
VL  - 8
IS  - 1
PB  - BioMed Central
PY  - 2008
ER  - 

TY  - JOUR
AB  - The Kit gene encodes a receptor tyrosine kinase involved in various biological processes including melanogenesis, hematopoiesis and gametogenesis in mice and human. A large number of Kit mutants has been described so far showing the pleiotropic phenotypes associated with partial loss-of-function of the gene. Hypomorphic mutations can induce a light coat color phenotype while complete lack of KIT function interferes with embryogenesis. Interestingly several intermediate hypomorphic mutations induced in addition growth retardation and post-natal mortality.
AU  - Magnol, L.*
AU  - Chevallier, M.C.*
AU  - Nalesso, V.*
AU  - Retif, S.*
AU  - Fuchs, H.
AU  - Klempt, M.
AU  - Pereira, P.*
AU  - Riottot, M.*
AU  - Andrzejewski, S.*
AU  - Doan, B.T.*
AU  - Panthier, J.J.*
AU  - Puech, A.*
AU  - Beloeil, J.C.*
AU  - Hrabě de Angelis, M.
AU  - Herault, Y.*
C1  - 5198
C2  - 24534
TI  - KIT is required for hepatic function during mouse post-natal development.
JO  - BMC Dev. Biol.
VL  - 7
PB  - BioMed Central
PY  - 2007
ER  - 

TY  - JOUR
AB  - Expression of the mouse Delta-like 1 (Dll1) gene in the presomitic mesoderm and in the caudal halves of somites of the developing embryo is required for the formation of epithelial somites and for the maintenance of caudal somite identity, respectively. The rostro-caudal polarity of somites is initiated early on within the presomitic mesoderm in nascent somites. Here we have investigated the requirement of restricted Dll1 expression in caudal somite compartments for the maintenance of rostro-caudal somite polarity and the morphogenesis of the axial skeleton. We did this by overexpressing a functional copy of the Dll1 gene throughout the paraxial mesoderm, in particular in anterior somite compartments, during somitogenesis in transgenic mice.
AU  - Teppner, I.
AU  - Becker, S.
AU  - Hrabě de Angelis, M.
AU  - Gossler, A.*
AU  - Beckers, J.
C1  - 5842
C2  - 24535
TI  - Compartmentalised expression of Delta-like 1 in epithelial somites is required for the formation of intervertebral joints.
JO  - BMC Dev. Biol.
VL  - 7
PB  - BioMed Central
PY  - 2007
ER  -