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 enforce 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 STAM1 functions in determining the ventral spinal MN axonal projections. STAM1 is co-expressed with Hrs in embryonic spinal MNs, and knock-down of STAM1 in the developing chick spinal cord results in down-regulation of the expression of CXCR4, 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 critical for the ventral motor axon trajectory. Our results reveal a critical regulatory axis for the ventral axonal trajectory of developing spinal MNs, consisting of the Isl1-Lhx3 complex, STAM1 and CXCR4.