Sox1 Maintains the Undifferentiated State of Cortical Neural Progenitor Cells via the Suppression of Prox1-Mediated Cell Cycle Exit and Neurogenesis

Abstract

Neural stem/progenitor cells maintain their identity via continuous self-renewal and suppression of differentiation. Gain-of-function experiments in the chick revealed an involvement for Sox1-3 transcription factors in the maintenance of the undifferentiated neural progenitor (NP) identity. However, the mechanism(s) employed by each factor has not been resolved. Here, we derived cortical neural/ stem progenitor cells from wild-type and Sox1-null mouse embryos and found that Sox1 plays a key role in the suppression of neurogenic cell divisions. Loss of Sox1 leads to progressive depletion of self-renewing cells, elongation of the cell cycle of proliferating cells, and significant increase in the number of cells exiting the cell cycle. In proliferating NP cells, Sox1 acts via a prospero-related homeobox 1 (Prox1)-mediated pathway to block cell cycle exit that leads to neuronal differentiation in vivo and in vitro. Thus, our results demonstrate that Sox1 regulates the size of the cortical NP pool via suppression of Prox1-mediated neurogenic cell divisions. STEM CELLS 2011;29:89-98 Disclosure of potential conflicts of interest is found at the end of this article.

The miR 302-367 cluster drastically affects self-renewal and infiltration properties of glioma-initiating cells through CXCR4 repression and consequent disruption of the SHH-GLI-NANOG network

“…Stable expression of the miR-302-367 cluster was sufficient to strongly inhibit the clonogenicity of GiCs and to promote loss of stem-like proteins including Oct4 and Nanog, 13,21 as well as Sox1 and SHH -known to be involved in adult normal neural stem cell and cancer stem cells self-renewal and maintenance. 15,[22][23][24][25][26][27] Consistent with our results, a previous report showed the importance of the miR-302-367 in cell differentiation by describing its role in the promotion of mesendodermal fate specification. 28 On the other hand, other reports described the miR-302-367 cluster as a stemness determinant in human embryonic stem cells (ESC) 29 and in inducible pluripotent stem cells (IPS) derived from human skin cancer cells.…”

Sox1 marks an activated neural stem/progenitor cell in the hippocampus

“…The only non-neural role described for SOX1 is in the developing eye lens, where SOX1 has been shown to regulate the -crystallin genes (Kamachi et al, 1998;Nishiguchi et al, 1998). Contradictory reports claim a role for SOX1 in neural lineage commitment and differentiation (Pevny et al, 1998;Kan et al, 2004;Ekonomou et al, 2005) versus maintenance of the progenitor pool (Bylund et al, 2003;Suter et al, 2009;Elkouris et al, 2011). A model reconciling both scenarios has been proposed whereby SOX1 plays an initial role in maintenance of division in the progenitor pool, but, upon continued expression, leads to neuronal differentiation (Kan et al, 2007).…”

Loss ofProx1in striated muscle causes slow to fast skeletal muscle fiber conversion and dilated cardiomyopathy

“…D uring mouse embryogenesis, Prospero-related homeobox factor 1 (Prox1) regulates lymphatic specification, neuronal development, and the genesis of the liver and pancreas (1)(2)(3)(4). Recently, Prospero-related homeobox factor 1 (Prox1) expression was shown to be enriched in murine slow-twitch skeletal muscle (5), and this is conserved in the zebrafish, where Prox1 is required for slow-twitch myofibril assembly (6).…”