The proneural determinant MASH 1 regulates forebrain Dlx 1 / 2 expression through the I 12 b intergenic enhancer

INTRODUCTION The establishment of a diversity of neuronal cell types in the central nervous system requires complex genetic regulatory mechanisms. Through combinatorial codes of transcription factors, neural progenitor cells commit themselves to a specific neuronal cell fate (Briscoe and Ericson, 2001). Recent studies have revealed that the developing vertebrate brain can be subdivided into multiple regions based on genetic interactions between genes involved in neural differentiation (Manuel and Price, 2005; Pasini and Wilkinson, 2002; Trujillo et al., 2005). The fate of neuronal progenitors present in these defined regions is controlled by distinct regional molecular microenvironments that give them their own identity. Thus, characterization of the different genetic interactions controlling the differentiation of the neuronal progenitors will provide new insights in the understanding of brain development and various neurological disorders. The homeobox genes of the Dlx family, which encode homeodomain-containing transcription factors, play an important role during the development of the forebrain (Bendall and AbateShen, 2000; Panganiban and Rubenstein, 2002; Zerucha and Ekker, 2000). This family comprises six members in mammals (Stock et al., 1996), organized as three bigene clusters – Dlx1/2, Dlx3/4 and Dlx5/6 – in an inverted and convergent configuration. Of the six mammalian Dlx genes, only Dlx1, Dlx2, Dlx5 and Dlx6 are expressed in the telencephalon and in the diencephalon (Bulfone et al., 1993; Robinson et al., 1991; Liu et al., 1997; Eisenstat et al., 1999). Expression of the Dlx genes in the telencephalon is restricted to the differentiating GABAergic ( -aminobutyric acid releasing) projection neurons and interneurons (Anderson et al., 1997b; Stuehmer et al., 2002a; Stuehmer et al., 2002b). Most of these neurons are born in the ventricular and subventricular zones (VZ and SVZ, respectively) of the lateral and medial ganglionic eminences (LGE and MGE, respectively). Soon after, they undergo a radial or a tangential migration through the SVZ to their final destinations in the piriform, cerebral cortex, hippocampus and olfactory bulb (Anderson et al., 1997a; Chapouton et al., 1999; de Carlos et al., 1996; Lavdas et al., 1999; Sussel et al., 1999; Tamamaki et al., 1997; Tamamaki et al., 1999; Wichterle et al., 1999). Dlx genes have highly overlapping but distinct patterns of forebrain expression. As reviewed by Panganiban and Rubenstein, Dlx2 is mainly expressed in the VZ and SVZ of the MGE and LGE of the telencephalon of E12.5 mouse embryos, where early differentiation occurs (Panganiban and Rubenstein, 2002). Dlx1 expression is found in all three zones (ventricular, subventricular and mantle). Expression of Dlx5 and Dlx6 is confined to the more-differentiated migrating neurons found in the subventricular and mantle zones. The inactivation of individual Dlx genes implicated in forebrain development results in a subtle phenotype (Acampora et al., 1999; Anderson et al., 1997b; Qiu et al., 1997; Qiu et al., 1995; Robledo et al., 2002). For example, mice lacking Dlx1 display a reduction in calretinin+ (also known as calbindin 2 – Mouse Genome Informatics) and somatostatin+ interneuron subtypes (Cobos et al., 2005). Mutant mice harboring this subtype-specific loss of interneurons show behavioral and histological signs of epilepsy. Inactivating the function of both Dlx1 and Dlx2 results in a massive reduction of GABAergic interneurons of the cerebral cortex, which is mainly due to a lack of tangential migration of the immature interneurons born in the VZ and SVZ of the ventral The proneural determinant MASH1 regulates forebrain Dlx1/2 expression through the I12b intergenic enhancer