, 1996; Manuel and Price, 2005; Georgala et al., 2011b). Several studies have implicated Pax6 in the regulation of neural progenitor proliferation, but the nature and significance of this regulation are poorly understood and C646 cost its mechanism is unknown ( Estivill-Torrus et al., 2002, Manuel et al., 2007, Georgala et al., 2011a; Asami et al., 2011). Through a region-specific action on cell proliferation, Pax6 may influence many aspects of brain development, including major features

such as regional differences in the size and shape of brain structures. Our first aim was to examine the nature and significance of Pax6’s regulation of cortical progenitor proliferation by examining mouse models with either complete or conditional loss of FK228 manufacturer Pax6 function. Previous studies have suggested that gradients of Pax6 expression present across the cortex at early stages of corticogenesis are important for its regionalization in terms of later differentiation (Bishop et al., 2000), but whether these gradients cause regional effects on early proliferation is unclear. Moreover, the effects on proliferation of changes in these Pax6-expression gradients with age have not been explored. Our second aim was to explore the mechanisms by which Pax6 might regulate cortical progenitor proliferation. To do this, we used a more focused approach than that

employed in previous screens aimed at identifying Pax6-regulated genes (Holm et al., 2007; Sansom et al., 2009). To screen for genes whose expression levels in Pax6-expressing cortical progenitors depend on whether these cells express Pax6 protein or not, we isolated Pax6-expressing progenitors using a line of reporter mice carrying a YAC transgene (DTy54) that expresses GFP under the control of PAX6’s regulatory elements ( Tyas et al., 2006) irrespective of the status of the endogenous Pax6 locus. In these mice, GFP is expressed by Pax6-expressing cortical progenitors

but not by the postmitotic neurons they give rise to ( Tyas et al., 2006), allowing us to compare profiles of gene expression Thalidomide in equivalent populations. The discoveries we made led us to examine Pax6’s regulation of the expression of the cyclin-dependent kinase Cdk6. In mammals, the Cdks and their partners the cyclins are the primary regulators of transition through the cell cycle (Malumbres and Barbacid, 2005). D-type cyclins facilitate the progression of progenitors, including cortical progenitors, through G1, a critical stage that allows responses to signals inducing either commitment to further stages of the cell cycle or withdrawal from the cell cycle (Zetterberg et al., 1995; Glickstein et al., 2009; Dehay and Kennedy, 2007; Lange et al., 2009; Pilaz et al., 2009).