| Here I examine the genetic mechanisms that pattern the cerebral cortical domain in mouse embryonic development. I focus on the interaction of morphogenic signaling centers thought to contribute to telencephalic patterning. I begin by describing in detail the anatomical development of the signaling sources. Functional studies employ mutant mouse lines and in utero electroporation to address the roles of signaling mechanisms in the basic patterning process leading to formation of dorsal, layered cortex and ventral, non-layered basal ganglia. In resolution to a long-standing conundrum in neural development, I find that the dorsal telencephalic midline, including the BMP/WNT sources, develops independent of Shh and the Fgfs thought to be needed for cortical area patterning, as has been proposed. Through epistasis analysis of Shh;Gli3 compound mutants, I reconcile the role of Shh in dorsal-ventral patterning of the telencephalon with its patterning roles in other tissues. Previously, it was reported that GO acts to limit the ventralizing effects of Shh in the dorsal telencephalon. I find instead that Shh activity is not the cause of ventralization defects in GO mutants. Layered cortex formation occurs as a function of Gli3R dosage; in Shh mutants, Gli3R excess causes global cortex formation, while GO haploinsufficiency in Shh mutants disinhibits basal ganglia formation but is sufficient for dorsal cortex formation. Cortex formation is therefore a major, novel, Shh-independent function of Gli3R. This significantly enhances understanding of early telencephalic patterning as well as the cortical phenotype of holoprosencephaly (HPE), a devastating forebrain development defect in humans. I further use the holoprosencephalic Shh null mouse to show how major diencephalic defects observed in humans may originate in early embryonic patterning. I investigate potential mechanisms regulating the telencephalic FGF sources and extend previous findings supporting tight regulation by Shh and Gli3. In the absence of Gli3, the entire telencephalon expresses Fgfs, regardless of Shh. Pax2/5/8 are not required for Fgf8 induction, as in the isthmic organizer, and I hypothesize that positioning of the rostral telencephalic FGF source depends on Shh indirectly as a function of patterning of BMP inhibitors. Together, these studies clarify the genetic mechanisms of cerebral cortical development. |
