Sip1 regulates sequential fate decisions by feedback signaling from postmitotic neurons to progenitors

Abstract

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.

Generation of Multiple Classes of V0 Neurons in Zebrafish Spinal Cord: Progenitor Heterogeneity and Temporal Control of Neuronal Diversity

“…Temporal changes in gene expression within p0 progenitors for V0-eBs and V0-eDs may occur in zebrafish. Extrinsic factors could also influence cell-fate decisions, as are suggested to during cortical and retinal development (Cepko, 1999;Fukumitsu et al, 2006;Seuntjens et al, 2009). During p0/V0 development, for example, signals secreted by differentiated cells (e.g., V0-eBs) could act on progenitors to tune their lineages such that they preferentially generate V0-eDs in the later phase of neurogenesis.…”

A Novel Transient Glutamatergic Population Migrating from the Pallial–Subpallial Boundary Contributes to Neocortical Development

“…The distribution of CP transient neurons in all cortical territories by E14.5 together with the homogeneous defects of cortical thickness along the RC axis and the absence of an increase in cell death in E1-Ngn2/CRE;Dbx1 DTA mutants suggest that CP transient neurons might affect progenitors' proliferation/differentiation but not survival at midcorticogenesis. Indeed, a feedback control from the postmitotic compartment on the VZ has been suggested to affect the generation of later-born neurons (Polleux et al, 1998;Viti et al, 2003;Dehay and Kennedy, 2007) as well as the switch from neurogenesis to gliogenesis (Seuntjens et al, 2009). Nevertheless, the final positioning of CP transient neurons into the CP is also consistent with a function for CP transient neurons at late stages of development, such as in the establishment of transient connections.…”

Developmental control of cortico-cerebral astrogenesis

“…Fgf2 and Egf stimulate proliferation of neonatal rodent astroblasts (Mayer et al, 2009;Riboni et al, 2001). Fibroblast growth factor 9 (Fgf9) promotes a substantial expansion of the perinatal astrogenic proliferating pool (Seuntjens et al, 2009) and delays terminal differentiation of mature astrocytes (Lum et al, 2009). Smad interacting protein 1 (Sip1) TF limits astroblasts proliferation, possibly by inhibiting Fgf9 expression (Seuntjens et al, 2009).…”