The fate of cortical progenitors, which progressively generate neurons and glial cells during development, is determined by temporally and spatially regulated signaling mechanisms. We found that the transcription factor Sip1 (Zfhx1b), which is produced at high levels in postmitotic neocortical neurons, regulates progenitor fate non-cell autonomously. Conditional deletion of Sip1 in young neurons induced premature production of upper-layer neurons at the expense of deep layers, precocious and increased generation of glial precursors, and enhanced postnatal astrocytogenesis. The premature upper-layer generation coincided with overexpression of the neurotrophin-3 (Ntf3) gene and upregulation of fibroblast growth factor 9 (Fgf9) gene expression preceded precocious gliogenesis. Exogenous application of Fgf9 to mouse cortical slices induced excessive generation of glial precursors in the germinal zone. Our data suggest that Sip1 restrains the production of signaling factors in postmitotic neurons that feed back to progenitors to regulate the timing of cell fate switch and the number of neurons and glial cells throughout corticogenesis.

SUMMARYDuring development, spinal motoneurons (MNs) diversify into a variety of subtypes that are specifically dedicated to the motor control of particular sets of skeletal muscles or visceral organs. MN diversification depends on the coordinated action of several transcriptional regulators including the LIM-HD factor Isl1, which is crucial for MN survival and fate determination. However, how these regulators cooperate to establish each MN subtype remains poorly understood. Here, using phenotypic analyses of single or compound mutant mouse embryos combined with gain-of-function experiments in chick embryonic spinal cord, we demonstrate that the transcriptional activators of the Onecut family critically regulate MN subtype diversification during spinal cord development. We provide evidence that Onecut factors directly stimulate Isl1 expression in specific MN subtypes and are therefore required to maintain Isl1 production at the time of MN diversification. In the absence of Onecut factors, we observed major alterations in MN fate decision characterized by the conversion of somatic to visceral MNs at the thoracic levels of the spinal cord and of medial to lateral MNs in the motor columns that innervate the limbs. Furthermore, we identify Sip1 (Zeb2) as a novel developmental regulator of visceral MN differentiation. Taken together, these data elucidate a comprehensive model wherein Onecut factors control multiple aspects of MN subtype diversification. They also shed light on the late roles of Isl1 in MN fate decision.

Signaling by the many ligands of the TGFβ family strongly converges towards only five receptor-activated, intracellular Smad proteins, which fall into two classes i.e. Smad2/3 and Smad1/5/8, respectively. These Smads bind to a surprisingly high number of Smad-interacting proteins (SIPs), many of which are transcription factors (TFs) that co-operate in Smad-controlled target gene transcription in a cell type and context specific manner. A combination of functional analyses in vivo as well as in cell cultures and biochemical studies has revealed the enormous versatility of the Smad proteins. Smads and their SIPs regulate diverse molecular and cellular processes and are also directly relevant to development and disease. In this survey, we selected appropriate examples on the BMP-Smads, with emphasis on Smad1 and Smad5, and on a number of SIPs, i.e. the CPSF subunit Smicl, Ttrap (Tdp2) and Sip1 (Zeb2, Zfhx1b) from our own research carried out in three different vertebrate models.

DEVELOPMENT 3399 RESEARCH ARTICLE INTRODUCTIONIn mouse embryos, extra-embryonic mesoderm cells of the prospective visceral yolk sac, chorion, allantois and amnion are among the first mesoderm cells to emerge early at gastrulation. Cell labelling studies have shown that a population of posterior and posterolateral epiblast cells that enters the primitive streak proximally will give rise to this extra-embryonic mesoderm and also to primordial germ cells (PGCs) (Lawson and Hage, 1994;Parameswaran and Tam, 1995;Kinder et al., 1999). Genetic evidence and epiblast culture experiments have shown that germ cell competence and formation of the allantois are induced in the proximal epiblast before gastrulation, in response to bone morphogenetic proteins (Bmps) produced in the extra-embryonic ectoderm, but depend also on the presence of visceral endoderm (reviewed by Zhao, 2003;de Sousa Lopes et al., 2004).Bmps are ligands of the transforming growth factor ␤ (Tgf␤) family that use various receptor complexes to directly activate intracellular effector proteins (Smad1/5/8). Smads transmit the signal to the nucleus and participate in the regulation of target gene expression (Shi and Massagué, 2003). Analysis of conventional knockout mice showed that the repertoire of Bmp signalling proteins involved in PGC induction comprise Bmps (Bmp2, -4 and -8b), a type I Bmp receptor (Alk2; Acvr1 -Mouse Genome Informatics) and two Bmp-Smads (Smad1/5) (Lawson et al., 1999;Ying et al., 2000;Chang and Matzuk, 2001;Tremblay et al., 2001;Hayashi et al., 2002;de Sousa Lopes et al., 2004;Okamura et al., 2005). Recently, it was shown that Blimp1 (Prdm1 -Mouse Genome Informatics), a transcriptional regulator thought to be induced by Bmp4, is a key regulator of germ cell specification (Vincent et al., 2005;Ohinata et al., 2005). Subsequent PGC localization and survival, as well as allantois differentiation, also depend on the presence of Bmp4 in the extra-embryonic mesoderm (Fujiwara et al., 2001).Several Bmps have been implicated in the specification and growth of extra-embryonic mesoderm. The induction of the allantois crucially depends on Bmp4 (Winnier et al., 1995;Fujiwara et al., 2001), and on Alk2-mediated signalling in visceral endoderm (Mishina et al., 1999;Gu et al., 1999). Bmp5;Bmp7 double mutant mouse embryos display impaired allantois maturation (Solloway and Robertson, 1999). Bmp2 plays a unique role in amnion development, as the pro-amniotic canal does not close in Bmp2 mutant mice, which has been ascribed to reduced and thus insufficient production of extra-embryonic mesoderm (Zhang and Bradley, 1996).Smad1 and Smad5 null embryos die at mid-gestation and have defects in PGC specification and allocation, and in the development of extra-embryonic tissues (Chang et al., 1999;Chang et al., 2000;Yang et al., 1999;Lechleider et al., 2001;Tremblay et al., 2001;Hayashi et al., 2002;Umans et al., 2003). The presence on the amnion of aggregates of cells that contain ectopic primitive red blood cells, and endothelial and PGC-like cells, is a un...