The central focus of the laboratory is to understand the role of inductive regulation of gene expression in the development and maintenance of the nervous system. We study this issue primarily during the initial patterning and differentiation of the mammalian forebrain. We have shown that RA-mediated inductive interactions guide the development of a distinct functional subdivision of the forebrain, the olfactory bulb, as well as its primary source of innervation, the olfactory epithelium. Furthermore, our results indicate that these inductive interactions are formally similar to those in the limbs, the branchial arches and the aortic arches. Thus, in all of these sites, RA, sonic hedgehog, the FGFs and the BMPs act to pattern downstream genes and influence subsequent morphogenesis and differentiation. We are now asking what the specific downstream target genes of early RA signals during forebrain development. We are simultaneously trying to establish the roles of potential target genes in establishing neuronal identify, influencing axon growth and guidance, and determining target selection and patterns of connectivity in the forebrain. These genes include several mouse homologues of human genes found on human chromosome 22q11. Heterozygous deletion of 22q11 in humans leads to phenotypic anomalies in the limbs, branchial arches, aortic arches and the forebrain.
A second focus for the lab is to understand how RA-signaling in the adult nervous system acts to mediate neuronal plasticity and regeneration. We have found that RA mediated gene expression is retained at two well established sites of plasticity in the central nervous system. The first is in the olfactory epithelium where there is constant regeneration of primary sensory neurons, and the second is in the dorsal horn of the spinal cord where neurons modify their expression of a number of genes in response to peripheral injury or trauma. Both of these neuronal populations receive RA signals during development, and we are currently evaluating the role of continued RA-mediated gene expression for regeneration and plasticity in the adult.
