The coordinated generation of specialized groups of spinal motor neurons during development of the central nervous system is essential for the assembly of functional neural circuits. Analysis to date hasfocused on the role of the signaling molecule shh in motor neuron specification however increasing evidencesuggests that other inductive molecules may play pivotal roles in their development. The dynamicspatiotemporal expression of RALDH2, the major synthetic enzyme for retinoic acid suggests that retinoidsignaling is required at defined stages in the sequential development of motor neurons. However, loss offunction studies have not been informative due to the early lethality of RALDH2 null embryos. This proposalaims to test the hypothesis that retinoids are required at specific stages of motor neuron development usinggenetic strategies in the mouse to bypass the early lethality of RALDH2 mutants. Tissue specific knockouts of RALDH2 will be constructed and analyzed to first assess the contribution of paraxial mesoderm derived retinoids to motor neuron generation and column induction and second, to determine if motor neuron derived retinoid signaling is necessary for motor column, motor division and motor pool determination. Finally, four prospective target genes for RALDH2 have been isolated using differential screening approaches and experiments outlined here will focus on functional analyses to determine the potential role of two of these genes in motor neuron specification. Taken together, these experiments aim to define the contribution of retinoic acid signaling to motor neuron development with the ultimate aim of assembling a molecular pathway of retinoid dependent events required for their specification during embryogenesis. Understanding the processes by which motor neuron specification occurs may provide insight into the basis of motor neuron degenerative diseases such as amyotrophic lateral sclerosis or the spinal muscular atrophies. This in turn may lead to the design of innovative treatments for these diseases in the future which may incorporate the use of stem cell technology.
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