Retinoic acid functions in the proliferation, survival, and cell fate specification of progenitors in the developing telencephalon

Retinoic acid (RA) signaling has multiple critical roles in the developing central nervous system. These include well-established roles in patterning, cell-fate specification, and differentiation of neurons in the spinal cord. Components of the RA signaling pathway are expressed in the developing forebrain, and multiple lines of evidence indicate that RA signaling is present and active during development of the telencephalon. Conventional models of loss of RA function, which rely on the use of null alleles of the RA synthetic enzymes, the RALDHs, are of limited value in the study of RA functions in the developing telencephalon, due to their early embryonic lethality and the lack of clarity as to the identity of the relevant enzyme at different stages of development. We have constructed a mouse that expresses a conditional allele of the dominant negative retinoic acid repector, RAR403, in order to define the roles of RA in the developing telencephalon (R26RAR403). Using the R26RAR403 mouse model to induce conditional disruption of RA signaling, we have determined that RA plays critical roles in proliferation and survival of telencephalic progenitors at early stages in development. At intermediate stages, RA signaling is necessary for the differentiation of Lhx6+ cells that will give rise to populations of cortical inhibitory interneurons, from Nkx2.1+ progenitors. We have further used this model to study the effects of the ablation of RA signaling on complex behaviors in adult mice, focusing on aggression.