Grant: Discovery Grants Program - Individual

Precise organization of neural circuits ensures proper functioning of the central nervous system (CNS). Assembly of those circuits requires correct specification of neuronal populations defined during development. One goal of my research is to understand developmental processes underlying formation of functional groups of spinal cord neurons. Different progenitor domains in the embryonic spinal cord give rise to motor neurons (MNs) and different interneuron (IN) classes, each with a unique molecular profile. Distinct types of spinal INs emerge from those progenitor domains, and, as recently revealed, they then undergo further subdivision to form highly heterogeneous populations. Adding another layer of complicity of spinal circuits, studies have shown that motor neuron pools and interneuron components vary in different spinal segments corresponding to the body parts that they control. As yet, however, little is known about molecular mechanisms that govern these processes.        My lab focuses on an IN group known as V3s as a model system to study subdivision of spinal INs. V3 INs arise from the most ventral progenitor domain, p3, and express the Sim1 transcription factor (TF) at early postmitotic stages. V3 INs are glutamatergic and commissural. We previously showed that in mice genetic deletion of the entire V3 population prevents animals from exhibiting robust and stable gait. We have demonstrated that, in the rostral lumbar region, V3 INs present multiple subpopulations according to their soma location, physiological and morphological properties and axon projection patterns. More excitingly, our initial screening has identified 5 TFs that potentially define 5 subpopulations in the higher lumbar regions. Even though we have observed the distribution pattern of V3 INs, like MNs, vary significantly in different spinal segments, we know little about components of V3 subpopulations in each segment. In addition, our most recent studies suggest that lumbar V3 INs are generated in two time-windows during development, and Sim1 played different roles in regulating the establishment of subpopulations with different birthdays. In our RNA sequencing study, we found that the Sim1 deletion changed the expression of many Hox genes. Therefore, we propose to systematically characterize V3 subpopulations in each spinal segment and determine the function of Sim1 and Hox TFs alone and their interaction in defining the segmental V3 diversity during development. To do so, we will use transgenic mice to trace V3 INs in wild-type control and Sim1- or Hoxc9-deficient mice to conduct the following studies: Aim I Characterize molecularly defined V3 subpopulations at different spinal segments Aim II Assess the functions of Sim1 in defining the identity and cellular properties of V3 subpopulations and their expression of Hox genes in different spinal segments. Aim III Investigate the function of Hoxc9 in regulating segmental V3 diversity.