DETERMINING THE TRANSCRIPTIONAL REGULATION & CELL SIGNALING EVENTS THAT SHAPE TH

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. A diverse array of neurons is essential for mammalian nervous system function. It is well known that the loss or dysfunction of specific subsets of neurons causes distinct neurological disorders. Parkinson's disease which has a devastating and negative impact on human health is the result of the degeneration of midbrain dopamine neurons of the substantia nigra, which are positioned in the lateral midbrain. The loss of substantia nigra dopamine neurons results in the inability to properly control movement. A current line of treatment proposed to treat Parkinson's disease is to use embryonic stem cell or induced pluripotent stem cell based therapy. The fundamental concept using cell based therapies is to transplant dopamine neuron precursors into patients with Parkinson's disease. A surrogate to test these approaches is transplant dopamine neuron precursors into animal models with midbrain dopamine neuron loss. However, a significant knowledge gap is that we do not understand how substantia nigra neurons are established during mammalian development, which translates into a problem of how to make the appropriate type of dopamine neuron. These deficits need to be addressed to design effective cell-based therapies to treat neurodegenerative diseases like Parkinson's disease. Currently there is no protocol to effectively instruct stem cells to acquire the most appropriate fate to ameliorate MbDA neuron-specific diseases. We have identified the dopamine neuron progenitor pool in vivo and determined that these progenitors express the gene Wnt1 during multiple critical steps for dopamine neuron development. The purpose of this proposal is to establish the molecular identity of Wnt1-expressing progenitors that contribute to developing dopamine neurons and to identify how WNT signaling specifies MbDA neuron progenitors. The studies in this proposal forge a link between the concept of cell fate specification and the problem of how distinct neuronal subtypes are established. An expected outcome is that we will elucidate regulatory components used to control the development of MbDA neuron subtypes from a complex progenitor pool. The positive impact of this application is that by uncovering how subtypes are allocated, we will provide a molecular scaffold that can be exploited to effectively guide stem cells to acquire a unique MbDA identity.