The metazoans interpret exogenous stimuli by the assembly of protein complexes that initiate and sustain the process of signal transduction. Such principles have wide-ranging effects on the fundamental development of neurons, including neurogenesis, migration, differentiation, programmed cell death, and synaptic connectivity. While there has been tremendous information about the mechanisms of signaling complexes on the cell membrane and in cytoplasm, much less is known about how these signals are transmitted to the nucleus to regulate transcriptional control of gene expression.
Research in my laboratory centers on the mechanisms by which transcriptional machinery regulates gene expression in response to trophic factors. One major focus has been to understand the role of a transcriptional cofactor, homeodomain protein kinase 2 (HIPK2), in trophic factor-dependent survival and cell death in sensory and midbrain dopamine (DA) neurons. Our results indicate that HIPK2 regulates programmed cell death in sensory neurons by controlling the expression of prosurvival genes. More recent results further reveal the upstream signaling pathways of HIPK2 and indicate that HIPK2 interacts with receptor-regulated Smads (R-Smads) and is required for DA neurons to respond to the survival signals from TGF?. As a consequence, DA neurons lacking HIPK2 show a selective failure of survival in TGF?, but not in other trophic factors. Due to this defect, HIPK2 mutants lose a significant number of DA neurons and show neurological phenotype resembling patients with Parkinson’s disease. Consistent with these results, mice lacking TGF?3 also show DA neuron phenotype similar to that in Hipk2 mutants.
These results lead us to hypothesize that TGFbeta-dependent signaling mechanisms may have broader functions in regulating different aspects of development in DA neurons. Future directions include (1) further studies on the role of different TGFbeta and HIPK isoforms in regulating neurogenesis of DA neurons, (2) identification of additional trophic factors that regulate the development of DA neurons, and (3) investigation of the TGFbeta-HIPK2 signaling mechanisms as a potential therapeutic targets for Parkinson’s disease.