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

Abstract

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.

SARS-CoV-2 3CLpro Main Protease Drives Cytoskeletal Reorganization and Tunnelling Nanotube Formation for Stealth Intercellular Infection

“…Over 50% of the 259 host cell protein interactors of SARS-CoV-2 3CL pro were associated with the cytoskeleton. Many of these are 3CL pro substrates with roles in regulating the formation of cell protrusions, including filipodia and dendrites, e.g., LASP1 39 , NUMA1 70 , drebrin 49 , and STAM 67 . The Arp2/3 complex is central to the formation of cellular protrusions since it nucleates branched actin assembly that provides the pushing force for plasma membrane deformation 71 .…”

“…Knockdown of signal transducing adapter molecule 1 (STAM) results in increased length of cell projections 67 , suggesting that STAM is inhibitory. STAM is a component of the endosomal sorting complexes required for transport (ESCRT)-0 complex that mediates membrane remodelling, vesicular transport and autophagy, and is hijacked by enveloped viruses to mediate budding 68 .…”

Critical roles of ARHGAP36 as a signal transduction mediator of Shh pathway in lateral motor columnar specification

“…ChIP was performed in mouse embryonic spinal cords as described previously (Nam and Lee, 2016; Cho et al, 2014; Lee et al, 2013). The spinal cords were microdissected from E12.5 mouse embryos and cells were dissociated and subjected to ChIP assays.…”

“…Genome-wide analyses of the Isl1-Lhx3 complex binding sites from chromatin immunoprecipitation-sequencing (ChIP-seq) datasets (Lee et al, 2013; Mazzoni et al, 2013) combined with MN transcriptome analyses (Lee et al, 2012; Mazzoni et al, 2013) identified many novel signaling pathways and regulators that are directly regulated by the Isl1-Lhx3 complex. Studies of individual target genes of the Isl1-Lhx3 complex in MN specification uncovered critical effector genes in MN specification such as genes involved in cholinergic neuronal identity determination (Cho et al, 2014), miR-218 as a downstream effector of Isl1-Lhx3 complex (Thiebes et al, 2015) and STAM1 as an endosomal sorting machinery necessary for ventral motor axon projection (Nam and Lee, 2016).…”