12-P012 A bioinformatic and in situ screen for novel axon guidance molecules

The forebrain cholinergic system consists of the cholinergic interneurons of the striatum and projection neurons that are distributed in loosely defined groups along the basal forebrain. Forebrain cholinergic neurons (FCNs) are born between E11 and E15, begin to express cholinergic markers at late embryonic stages, invade their projection target areas postnatally and continue to mature for weeks after birth. Little is known about the cell-intrinsic factors that regulate this process. FCNs derive from NKX2.1 precursors that upon exiting the cell cycle express the LIM homeodomain proteins LHX7 and ISL1. Our group and others have shown that deletion of Lhx7 leads to a reduction of 80% in the number of FCNs. In particular, studies from our group have demonstrated that in the striatum of Lhx7 null mice the missing cholinergic interneurons are respecified as GABAergic interneurons (Fragkouli et al., submitted). Similarly, deletion of Isl1 results in a dramatic reduction in the number of FCNs . To gain further insight into the role of LHX7 and ISL1 in the development and maintenance of the FCNs we have generated and analyzed an Lhx7 conditional knockout. Here we describe the effect of deleting Lhx7 at embryonic and postnatal stages using the Nkx2.1-Cre and Isl1-Cre lines and an inducible Cre line. We also report on studies addressing the role of Isl1 in the development of FCNs. We discuss the role of LIM HD transcription factors in the development of FCNs and in the plasticity of cholinergic phenotype at different pre and postnatal stages.