(click on picture for caption)

Cell fate specification in the central nervous system

      The central nervous system consists of many different cell types which during embryonic development need to be coordinately generated and specified with regard to identity, final settling position and axonal trajectory in order to establish functional neural circuits. The focus of my laboratory is directed towards understanding the signaling events and molecular mechanisms involved in neuronal fate specification. Our investigations concentrate on the developing chick and mouse embryo using an integrated approach involving molecular biology, cell biology, in ovo electroporation of chick embryos, mouse genetics and behavior.

     We have recently shown that retinoic acid (RA), a small lipophilic signaling molecule, is critical for the generation and subtype specification of particular groups of spinal motor neurons. Our current work using mouse genetics suggests that the highly regulated temporal and spatial expression of the key retinoid synthetic enzyme RALDH2 is directly responsible for generating local sources of RA necessary for motor neuron specification. The retinoid signal is transduced by nuclear receptors RAR and RXR, which bind to retinoid response elements upstream of target genes. One major area of interest in the lab is the identification and characterization of retinoid responsive genes involved in spinal motor neuron specification. Spinal motor neuron development is highly conserved between species. This allows us to utilize both chick and mouse models to identify key processes and dissect out molecular networks which are almost certainly to be conserved in humans. We have carried out and are continuing a differential subtraction screen using chick neural explants and have isolated several promising candidates which show motor neuron specific expression. Ongoing characterization of these novel potential targets includes in vivo gain of function and loss of function analysis using in ovo electroporation in the chick. Once functionality is determined in the avian system, future studies on bona fide target genes will be carried out using genetic approaches in the mouse. Our aim is thus to define molecular events which are critical in motor neuron development with the ultimate goal of further understanding both the basis of spinal motor neuron degenerative diseases such as ALS and in devising potential stem cell therapies for treatment.

     We have recently begun exploring if RA signaling is also required for cell specification events in other regions of the central nervous system. Analysis of reporter mice sensitive to RA reveals high amounts of RA in the developing forebrain at early stages in development, in structures which are disproportionately affected in diseases such as schizophrenia and epilepsy. We have initiated studies using mouse genetics to evaluate the in vivo contribution of RA signaling to the development of these structures during embryogenesis.