Defects in thalamocortical axon pathfinding correlate with altered cell domains in Mash-1-deficient mice

We have analyzed the pathfinding of thalamocortical axons (TCAs) from dorsa l thalamus to neocortex in relation to specific cell domains in the forebra in of wild-type and Mash-1-deficient mice. In wild-type mice, we identified four cell domains that constitute the proximal part of the TCA pathway. Th ese domains are distinguished by patterns of gene expression and by the pre sence of neurons retrogradely labeled from dorsal thalamus, Since the cells that form these domains are generated in forebrain proliferative zones tha t express high levels of Mash-1, we studied Mash-1 mutant mice to assess th e potential roles of these domains in TCA pathfinding. In null mutants, eac h of the domains is altered: the two Pax-6 domains, one in ventral thalamus and one in hypothalamus, are expanded in size; a complementary RPTP delta domain in ventral thalamus is correspondingly reduced and the normally grad ed expression of RPTP delta in that domain is no longer apparent. In ventra l telencephalon, a domain characterized in the wild type by Netrin-1 and Nk x2.1 expression and by retrogradely labeled neurons is absent in the mutant . Defects in TCA pathfinding are localized to the borders of each of these altered domains. Many TCAs fail to enter the expanded, ventral thalamic Pax -6 domain that constitutes the most proximal part of the TCA pathway, and f orm a dense whorl at the border between dorsal and ventral thalamus. A prop ortion of TCAs do extend further distally into ventral thalamus, but many o f these stall at an aberrant, abrupt border of high RPTP delta expression. A small proportion of TCAs extend around the RPTP delta domain and reach th e ventral thalamic-hypothalamic border, but few of these axons turn at that border to extend into the ventral telencephalon. These findings demonstrat e that Mash-1 is required for the normal development of cell domains that i n turn are required for normal TCA pathfinding. In addition, these findings support the hypothesis that ventral telencephalic neurons and their axons guide TCAs through ventral thalamus and into ventral telencephalon.