Mammalian hairy and Enhancer of Split Homolog 1 Regulates Differentiation of Retinal Neurons and Is Essential for Eye Morphogenesis

AbstractMammalian hairy and Enhancer of split homolog 1 (HES1), a basic helix-loop-helix factor gene, is expressed in retinal progenitor cells, and its expression decreases as differentiation proceeds. Retinal progenitor cells infected with HES1-transducing retrovirus did not differentiate into mature retinal cells, suggesting that persistent expression of HES1 blocks retinal development. In contrast, in the retina of HES1-null mutant mice, differentiation was accelerated, and rod and horizontal cells appeared prematurely and formed abnormal rosette-like structures. Lens and cornea development was also severely disturbed. Furthermore, in the mutant retina, bipolar cells extensively died and finally disappeared. These studies provide evidence that HES1 regulates differentiation of retinal neurons and is essential for eye morphogenesis

Goosecoid and HNF-3beta genetically interact to regulate neural tube patterning during mouse embryogenesis

The homeobox gene goosecoid (gsc) and the winged-helix gene Hepatic Nuclear Factor-3beta (HNF-3beta) are co-expressed in all three germ layers in the anterior primitive streak and at the rostral end of mouse embryos during gastrulation. In this paper, we have tested the possibility of functional synergism or redundancy between these two genes during embryogenesis by generating double-mutant mice for gsc and HNF-3beta. Double-mutant embryos of genotype gsc(-/-);HNF-3beta(+/-) show a new phenotype as early as embryonic days 8.75. Loss of Sonic hedgehog (Shh) and HNF-3beta expression was observed in the notochord and ventral neural tube of these embryos. These results indicate that gsc and HNF-3beta interact to regulate Shh expression and consequently dorsal-ventral patterning in the neural tube. In the forebrain of the mutant embryos, severe growth defects and absence of optic vesicles could involve loss of expression of fibroblast growth factor-8, in addition to Shh. Our results also suggest that interaction between gsc and HNF-3beta regulates other signalling molecules required for proper development of the foregut, branchial arches and heart

An essential function of the mitogen‐activated protein kinase Erk2 in mouse trophoblast development

The closely related mitogen-activated protein kinase isoforms extracellular signal-regulated kinase 1 (ERK1) and ERK2 have been implicated in the control of cell proliferation, differentiation and survival. However, the specific in vivo functions of the two ERK isoforms remain to be analysed. Here, we show that disruption of the Erk2 locus leads to embryonic lethality early in mouse development after the implantation stage. Erk2 mutant embryos fail to form the ectoplacental cone and extra-embryonic ectoderm, which give rise to mature trophoblast derivatives in the fetus. Analysis of chimeric embryos showed that Erk2 functions in a cell-autonomous manner during the development of extra-embryonic cell lineages. We also found that both Erk2 and Erk1 are widely expressed throughout early-stage embryos. The inability of Erk1 to compensate for Erk2 function suggests a specific function for Erk2 in normal trophoblast development in the mouse, probably in regulating the proliferation of polar trophectoderm cells

A gene network establishing polarity in the early mouse embryo

In mammalian embryos, molecular cross-talk with extraembryonic tissues is essential to elaborate the primary body axes. Here, we review a series of reciprocal interactions that occur shortly after implantation in the uterus, and discuss how they are integrated in a complex signaling network to establish antero-posterior and dorso-ventral polarity. At the heart of this signaling network is the TGFbeta-related protein Nodal which acts on extraembryonic tissues to induce positive and negative feedback regulators at opposite poles of the egg cylinder. This likely results in an activity gradient which is instrumental to pattern the embryo proper

ANALYSE DE LA FONCTION DES GENES HNF3 BETA, LIM1 ET OTX2 DANS L'ENDODERME VISCERAL ANTERIEUR DE L'EMBRYON DE SOURIS AU COURS DE LA GASTRULATION

STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Rôle du facteur de transcription Otx2 lors de la maintenance de l'identité du mésencéphale et de la différenciation neuronale dans le mésencéphale murin

Le facteur de transcription Otx2 détermine l'identité mésencéphalique face à l'identité métencéphalique (rhombencéphale antérieur) notamment en positionant et maintenant le centre organisateur de l'isthme au niveau de la frontière mésencéphalique/métencéphalique. Cependant le rôle de Otx2 n'est pas restreint à cette étape du développement comme le suggère la maintenance de son expression dans le mésence phale bien après l'établissement du centre organisateur de l'isthme. Pour étudier, le rôle plus tardif de Otx2 dans le mésencéphale, j'ai utilisé une stratégie d'invalidation conditionnelle du gène Otx2 à l'aide du système CRE-LoxP et je me suis plus particulièrement intéressé à l'étude de l'identité neuronale dans le mésencéphale en l'absence de Otx2. Suite à la perte de Otx2 dans les progéniteurs neuronaux, une partie d'entre eux adoptent un programme de différenciation caractéristique du rhombencéphale antérieur ou métencéphale : cellules cérébelleuses dorsalement et neurones sérotoninergiques ventralement. Nous avons montré que ce phénotype est indépendant de tout déplacement du centre organisateur de l'isthme dans le mésencéphale mutant. L'analyse de l'expression de différents gènes nous a permis de montrer que les progéniteurs mésencéphalique adoptent un programme de différenciation métencéphalique (cellules cérébelleuses et neurones sérotoninergiques) au dépend des programmes mésencéphaliques qui déterminent les différentes classes de neurones mésencéphaliques (neurones dopaminergiques, noyau rouge). Otx2 en réprimant les gènes Math1 (cervelet) et Nkx2-2 (neurones sérotoninergiques) dans les progéniteurs mésencéphaliques empêche la mise en place des programmes de différenciation rhombencéphalique. En résumé ce travail démontre que Otx2 est requis dansle mésencéphale après 10,5 jpc pour maintenir l'identité mésencéphalique des progéniteurs et réprimer tout programme de différenciation rhombencéphalique.The transcription factor Otx2 is required to determine mesencephalic versus metencephalic (anterior rhombencephalon) territory during embryogenesis. So far, this function of Otx2 involves positioning and maintaining the mid-hindbrain organizer (MHO) at the border between midbrain and anterior hindbrain. Otx2 expression is maintained in midbrain progenitors long after this organizer is established suggesting that Otx2 could play a role during neurogenesis. I used a conditional knock-out strategy (system CRE-LoxP) to study Otx2 function during neurogenesis in the neuroectoderme and my analysis is focused on neuronal identity in mesencephalon in absence of Otx2. Following Otx2 deletion in mesencephalic neuronal progenitors, some progenitors adopt a rhombencephalic fate that is normally repressed by Otx2 in mesencephalon. Indeed, ectopic cerebellar cells and ectopic serotonergic neurons are observed in dorsal and ventral mesencephalon respectively. Gene expression analysis show that the mesencephalic neuronal progenitors adopt rhombencephalic fate at the expanse of mesencephalic fate (dopaminergic and red nuclei neurons) and we conclude that Otx2 prevents the formation of cerebellar neurons and serotonergic neurons in midbrain presumably by repressing the expression of genes such as Math1 (cerebellum) and Nkx2-2 (serotonergic neurons) in progenitors. In summary, this work demonstrates that Otx2 is required in midbrain progenitors to maintain mesencephalic fate and repress rhombencephalic differentiation program independently of its earlier patterning function at the mid-hindbrain border.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Otx2 and HNF3beta genetically interact in anterior patterning

International audiencePatterning the developing nervous system in the mouse has been proposed to depend on two separate sources of signals, the anterior visceral endoderm (AVE) and the node or organizer. Mutation of the winged-helix gene HNF3beta leads to loss of the node and its derivatives, while mutation of the homeobox gene Otx2 results in loss of head structures, apparently at least partially because of defects in the AVE. To investigate the potential genetic interactions between the two signaling centers, we crossed Otx2+/- and HNF3beta+/- mice and found that very few Otx2+/-;HNF3beta+/- double heterozygous mutants survived to weaning. Normal Mendelian ratios of genotypes were observed during gestation, but more than half the double heterozygotes displayed a severe anterior patterning phenotype that would be incompatible with postnatal survival. The phenotype was characterized by varying degrees of holoprosencephaly, cyclopia with proboscis-like structures, and anterior forebrain truncations. Regional marker analysis revealed that ventral forebrain structures of Otx2+/-;HNF3beta+/- mutant embryos were most severely affected. Shh expression was completely absent in the anterior region of Otx2+/-;HNF3beta+/- embryos, suggesting that Otx2 and HNF3beta genetically interact, directly or indirectly, to regulate Shh expression in the anterior midline. In addition, the forebrain truncations suggest an involvement of both genes in anterior patterning, through their overlapping expression domains in either the AVE and/or the prechordal mesoderm

Cloning of the mouse Sef gene and comparative analysis of its expression with Fgf8 and Spry2 during embryogenesis

International audienceWe report the cloning and expression analysis of a mouse gene encoding a novel transmembrane protein. Expression of Sef is similar to that of Fgf8 and Spry2 during early embryogenesis, being prominent in the forebrain, mid-hindbrain boundary, branchial arches, somites, limb bud and tailbud of mouse embryos. These expression profiles indicate that Fgf8, Spry2 and Sef belong to a synexpression group and suggest that these genes may functionally interact during embryonic development. From E12.5 onwards, partially distinct patterns of expression of these genes are observed in the neuroepithelium, sense organs and endodermal-derived organs, that are known sites of expression of other Fgfs

Functional Redundancy of ERK1 and ERK2 MAP Kinases during Development

ERK1 and ERK2 are the effector kinases of the ERK1/2 MAP-kinase signaling pathway, which plays a central role in transducing signals controlling cell proliferation, differentiation, and survival. Deregulated activity of the ERK1/2 pathway is linked to a group of developmental syndromes and contributes to the pathogenesis of various human diseases. One fundamental question that remains unaddressed is whether ERK1 and ERK2 have evolved unique physiological functions or whether they are used redundantly to reach a threshold of global ERK activity. Here, we show that the extent of development of the mouse placenta and embryo bearing different combinations of Erk1 and Erk2 alleles is strictly correlated with total ERK1/2 activity. We further demonstrate that transgenic expression of ERK1 fully rescues the embryonic and placental developmental defects associated with the loss of ERK2. We conclude that ERK1 and ERK2 exert redundant functions in mouse development