The goal of this proposal is to study the molecular mechanisms underlying the establishment of somatosensory circuits in the mammalian brain. We recently identified a LIM homeobox transcription factor, Lmxlb, in the trigeminal brainstem nucleus principalis (PrV). Preliminary studies of Lmxlb knockout mice revealed profound deficits in many important aspects of PrV development, including its morphology, axonal guidance, gene regulation, cell survival, cell fate determination and whisker-related pattern formation. The expression of Drg11, the first identified transcription factor that has been shown to be essential for the development of the PrV-based lemniscal pathway (Ding et al. '03), is absent in the Lmxlb null PrV, but it appears to be normal in the TG. Several significant differences exist between Lmxlb and Drg11. First, Lmx1b does not appear to be expressed in the embryonic TG, unlike Drg11. Second, while Lmx1b and Drg11 mutants display similar gross abnormalities in the brainstem projections of V primary afferents, the Lmxlb null phenotype is much more severe and spans more developmental events than that of the Drg11 mutant, thus suggesting that the Lmx1b/Drg11 relationship is not a simple linear, mechanistically redundant one. Third, Lmx1b is now implicated in the specification of neurotransmitter fate in the PrV cells, whereas Drg11 is not. Prompted by these preliminary studies, we offer the general hypothesis that Lmxlb is an essential molecular regulator of the developing PrV-based primary afferent and lemniscal pathway. To test this general hypothesis, we have five Specific Aims.
Our first aim i s to test the specific hypothesis that Lmxlb is required for normal morphogenesis and migration of PrV cells.
Aim two is to test the hypothesis that Lmxlb controls the trajectories of the TG cell axons in the PrV and the thalamic projections of PrV efferents.
Aim three is to test the hypothesis that Lmxlb regulates downstream transcription factors (in addition to Drg11) and axonal guidance molecules in the developing PrV.
Aim four is to test the hypothesis that Lmxlb is required for the survival of developing PrV cells and preventing abnormal cell death rescues the formation of whisker-related patterns in the PrV of Lmxlb mutants.
Aim five is to test the hypothesis that Lmxlb specifies excitatory vs. inhibitory neurotransmitter phenotype in developing PrV cells.
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