Identification of STAM1 as a novel effector of ventral projection of spinal motor neurons.

During spinal cord development, motor neuron (MN) axons exit the spinal cord ventrally, although the molecular basis for this process remains poorly understood. STAM1 and HRS form a complex involved with endosomal targeting of cargo proteins, including the chemokine receptor CXCR4. Interestingly, the absence of CXCR4 signaling in spinal MNs is known to result in improper extension of the axons into the dorsal side of the spinal cord. Here, we report that the MN-specific ISL1-LHX3 complex directly transactivates the Stam1 gene and that STAM1 functions in determining the ventral spinal MN axonal projections. STAM1 is co-expressed with HRS in embryonic spinal MNs, and knockdown of STAM1 in the developing chick spinal cord results in downregulation of CXCR4 expression, accompanied by dorsally projecting motor axons. Interestingly, overexpression of STAM1 or CXCR4 also results in dorsal projection of motor axons, suggesting that proper CXCR4 protein level is necessary for the ventral motor axon trajectory. Our results reveal a crucial regulatory axis for the ventral axonal trajectory of developing spinal MNs, consisting of the ISL1-LHX3 complex, STAM1 and CXCR4.