The function of Sim1 in the development of different V3 subpopulations in the mouse spinal cord.

ZHANG, Y.; LANUZA, G.M.

San Diego, CA, USA

Congreso; Annual Meeting Society for Neuroscience; 2013

SfN

The V3 interneurons in the spinal cord are a group of excitatory commissural interneurons that play an important role in producing balanced and stable gaits in animals. In the developing mouse spinal cord, V3 interneurons arise from the most ventral progenitor domain, p3. V3 neurons begin entering the post-mitotic stage and expressing the transcription factor "single-minded 1" (Sim1) on embryonic day (E) 9.5 and continue until E16.5. V3 neurons migrate dorsally and laterally at E12.5, eventually at birth settling as clusters in Rexed?s Lamina VIII (ventral), VII-VI (intermediate), and IV-V (dorsal) regions. Although Sim1 has long been used as a molecular marker to identify V3 neurons in the spinal cord, its function during V3 development is still unknown. To reveal its function, in the current study, we have used mouse molecular genetics to knock out Sim1 and trace the fate of mutant V3 neurons along development. We found that in Sim1 mutants, V3 neurons are still generated and maintain their excitatory and commissural characteristics. However, mutant V3s showed several defects in their migration, axon projection pattern and electrophysiological properties. In general, in the absence of Sim1, V3 neurons don?t form well organized clusters during the migration. At p0, the dorsalsubgroup cells are largely absent, while intermediate cells are significantly increased. This result indicates that prospective dorsal Sim1 null cells might be stuck at the intermediate region. On the other hand, the number of ventral V3s remained unchanged, but we found a drastic decrease in their axonal projections at both E14.5 and P0. We further investigated the intrinsic properties of distinct V3 subsets. We found that Sim1-deficient V3 neurons had smaller membrane capacitance than in control V3 animals, corresponding to their less branched morphological structure. However, only the remaining dorsal V3s showed significantly decreased sag voltage at -120 mV membrane potential and a smaller spike frequency adaptation responding to suprathreshold pulses. These results strongly indicate that Sim1 is crucial for the migration and maturation of dorsal V3s, but more important for the axon out-growth of ventral V3 spinal interneurons.