Mechanisms Governing Neuronal Development

The proposed research is a continuation of our ongoing studies of the role of the bone morphogenetic proteins (BMPs) in neural progenitor cell lineage commitment and brain development. Specifically these studies will employ a combined in vitro/in vivo approach to define BMP target genes that mediate effects of the BMPs on brain development. The first set of studies will focus on the HRT family of genes which are induced in progenitor cells by BMP signaling. Although HRT1 and HRT2 are similar in function to other members of the Hes family of factors, HRT3 acts as a dominant negative inhibitor of other Hes family members. HRT3 promotes neuronal differentiation of progenitor cells and may mediate, in part, the proneuronal effects of BMP signaling. Importantly, HRT3 expression oscillates after BMP4 treatment of cultured progenitor cells and is out of phase with other oscillating genes including Hes 5 and Hes1. This may stabilize the oscillator which is hypothesized in the nervous system to keep some stem cells undifferentiated while other seemingly identical cells differentiate in response to epigenetic signals. The second set of studies will focus on the Iroquois genes, specifically Iroquois 1 (Irx1). BMP4 treatment of progenitor cells suppresses expression of Irx1. Irx1 is a TALE class homeodomain factor whose orthologues in Drosophila and Xenopus are critical for neurogenesis. We have found that Irx1 is expressed in the telencephalon in progenitor cells (ventricular zone) and in lower levels in cells committing to the neuronal phenotype. Irx1physically associates with another TALE class factor PBX1, and it also associates with HDAC3. Further, the complex associates with CBP, suggesting that it may have both stimulatory and inhibitory effects depending upon binding partners. Finally, Irx1 and PBX1 associate associate physically with Dlx1 and DIx2 providing a mechanism by which these transcription factors may regulate neural development. The proposed studies seek to define the role of Irx1 in development of the telencephalon and to define the molecular mechanisms underlying its actions.In a broader sense these studies seek to define the role of intercellular communication in development and function of the nervous system. It is hoped that these studies will indicate biochemical loci where therapeutic tintervention in disease processes may lead to a return to normal neuronal function.