Molecular Neurobiology, Cell DifferentiationThere are currently two major projects underway in the laboratory. The first deals with the physiological significance for multiple Na,K-ATPase (sodium pump) isoforms. The question we are trying to answer is whether different sodium pump genes encode subunits that have similar or distinct functional properties. To address this issue, we are studying sodium pumps in zebrafish, a model genetic organism. We have identified 15 sodium pump genes in fish. We are employing antisense morpholinos to knock down expression of different sodium pump genes, and assess whether gene knockdowns produce distinctive developmental or physiological defects. This type of approach has so far revealed novel roles for sodium pump genes in ear and heart development. Complementation analysis suggests that each of the genes is functionally distinct since they cannot substitute for each other in mRNA rescue experiments. While providing a basis for determining which sodium pump genes perform unique versus redundant functions, the gene knockdown approach has also allowed us to identify new and unexpected roles for sodium pump genes in development and cellular function.
The second area of inquiry concerns the regulation of dopaminergic neurotransmission. Deficits in dopamine neurotransmission contribute to the emotional and cognitive deficits manifest in schizophrenia. A primary focus of our work concerns the identification of dopamine receptor interacting proteins (DRIPs). Among these DRIPs are proteins that are likely to represent novel schizophrenia candidate genes. We are conducting protein interaction screens to systematically identify and characterize proteins that regulate dopamine receptor function in brain. Our screens have so far uncovered a cohort of DRIPs that play important roles in regulating dopamine receptor function. One class of DRIPs is involved in attaching dopamine receptors to the cytoskeleton and anchoring the receptor at sites of synaptic transmission. A second group of DRIPs appears to regulate the signaling properties of the receptor as well as receptor internalization and desensitization. Expression of at least two DRIPs is altered in patients with schizophrenia, suggesting that DRIPs may represent new molecular targets for the treatment of schizophrenia and other thought disorders. Finally, we are using the zebrafish system to identify mutants in dopamine receptor genes that will allow us to investigate the link between dopamine signaling and drug addiction and reward. | 
