The on/off of Pax6 controls the tempo of neuronal differentiation in the developing spinal cord

Abstract

During neurogenesis, complex networks of genes act sequentially to control neuronal differentiation. In the neural tube, the expression of Pax6, a paired-box-containing gene, just precedes the appearance of the first post-mitotic neurons. So far, its only reported function in the spinal cord is in specifying subsets of neurons. Here we address its possible function in controlling the balance between proliferation and commitment of neural progenitors. We report that increasing Pax6 level is sufficient to push neural progenitors toward cell cycle exit and neuronal commitment via Neurogenin 2 (Ngn2) upregulation. However, neuronal precursors maintaining Pax6(On) fail to perform neuronal differentiation. Conversely, turning off Pax6 function in these precursors is sufficient to provoke premature differentiation and the number of differentiated neurons depends of the amount of Pax6 protein. Moreover, we found that Pax6 expression involves negative feedback regulation by Ngn2 and this repression is critical for the proneural activity of Ngn2. We present a model in which the level of Pax6 activity first conditions the moment when a given progenitor will leave the cell cycle and second, the moment when a selected neuronal precursor will irreversibly differentiate.

Sp8 plays a supplementary role to Pax6 in establishing the pMN/p3 domain boundary in the spinal cord

“…S7C). This result is consistent with previous studies that have suggested that all neural progenitor markers are downregulated by high levels of Pax6 (Bel-Vialar et al, 2007).…”

Pax2 modulates proliferation during specification of the otic and epibranchial placodes

“…In addition, forced expression of Pax7 in satellite cells prevents their difference into myoblasts (Olguin and Olwin, 2004). Similarly the activity of Pax6 is involved in conferring progenitor status to neuronal populations in the spinal cord, cerebral cortex, adult hippocampus, and olfactory bulb (Grindley et al, 1995;Kohwi et al, 2005;Bel-Vialar et al, 2007;Tucker et al, 2008). Similarly, the expression of Pax2 and Pax8 is associated with proliferating progenitor populations in the developing kidney (Bouchard et al, 2002) and in the sensory patches of the inner ear (Li et al, 2004;Warchol and Richardson, 2009).…”

PAX6 (paired box 6)

“…Pax6 function in development of fundamental sensory processes and central nervous system, particularly of the photoreceptive organ, are remarkably conserved in evolution (Halder et al, 1995;Gehring et al, 2005). PAX6 funciton in development were found to be under control of Shh, notch and EGFR signaling (Ericson et al, 1997;Kumar and Moses, 2001;Onuma et al, 2002;Li and Lu, 2005), essential for neural stem cell proliferation, multipotency, and neurogenesis in many regions of the central nervous system (Warren et al, 1999;Bishop et al, 2000;Toresson et al, 2000;Marquardt et al, 2001;Yamasaki et al, 2001;Yun et al, 2001;Estivill-Torrus et al, 2002;Heins et al, 2002;Simpson and Price, 2002;Tyas et al, 2003;Collinson et al, 2004;Haubst et al, 2004;Nomura and Osumi, 2004;Schuurmans et al, 2004;Maekawa et al, 2005;Bel-Vialar et al, 2007;Duparc et al, 2007;Quinn et al, 2007;Canto-Soler et al, 2008;OronKarni et al, 2008;Osumi et al, 2008), and appears to control the balance between neural stem cell selfrenewal and neurogenesis under a dose-dependent manner (Sansom et al, 2009). PAX6 binds as a monomer to relatively long (15-22 bp) DNA binding sites, and the 14 aa insertion in the paired domain allows different binding affinity to DNA sequences between PAX6a and PAX6b (Epstein et al, 1994a;Epstein et al, 1994b).…”