Population-Specific Regulation of Chmp2b by Lbx1 during Onset of Synaptogenesis in Lateral Association Interneurons

Abstract

Chmp2b is closely related to Vps2, a key component of the yeast protein complex that creates the intralumenal vesicles of multivesicular bodies. Dominant negative mutations in Chmp2b cause autophagosome accumulation and neurodegenerative disease. Loss of Chmp2b causes failure of dendritic spine maturation in cultured neurons. The homeobox gene Lbx1 plays an essential role in specifying postmitotic dorsal interneuron populations during late pattern formation in the neural tube. We have discovered that Chmp2b is one of the most highly regulated cell-autonomous targets of Lbx1 in the embryonic mouse neural tube. Chmp2b was expressed and depended on Lbx1 in only two of the five nascent, Lbx1-expressing, postmitotic, dorsal interneuron populations. It was also expressed in neural tube cell populations that lacked Lbx1 protein. The observed population-specific expression of Chmp2b indicated that only certain population-specific combinations of sequence specific transcription factors allow Chmp2b expression. The cell populations that expressed Chmp2b corresponded, in time and location, to neurons that make the first synapses of the spinal cord. Chmp2b protein was transported into neurites within the motor- and association-neuropils, where the first synapses are known to form between E11.5 and E12.5 in mouse neural tubes. Selective, developmentally-specified gene expression of Chmp2b may therefore be used to endow particular neuronal populations with the ability to mature dendritic spines. Such a mechanism could explain how mammalian embryos reproducibly establish the disynaptic cutaneous reflex only between particular cell populations.

The role of CHMP2BIntron5 in autophagy and frontotemporal dementia

“…The CHMP2B Intron5 -mediated misregulation of diverse signaling pathways raises a broader question of why this mutant isoform only leads to FTD-3 in late, pre-senile adulthood when ESCRTs clearly regulate processes involved in early development (Rusten et al, 2012; Xu et al, 2012). It is also curious why only the brain, and only a subset of neurons, is affected by loss of ESCRT function, which controls essential processes in nearly all cell types.…”

Associations of LBX1 gene and adolescent idiopathic scoliosis susceptibility: a meta-analysis based on 34,626 subjects

“…The LBX1 gene locates on chromosome 10q24.31, and it is a hemeobox transcription factor [ 19 , 20 ]. It takes part in spinal cord differentiation and patterning, and somatosensory signal transduction.…”

Endosomal sorting complexes required for ESCRTing cells toward death during neurogenesis, neurodevelopment and neurodegeneration

“…Increasing evidences suggest that ESCRT‐III, especially CHMP2B effectuates the genesis and maturation of dendritic spines, and that its pathogenic mutants perturb this process. These morphological changes further translate into gross alterations in functional potentiation, synaptic plasticity and synaptic homeostasis, long before inducing massive neuronal death …”

“…These morphological changes further translate into gross alterations in functional potentiation, synaptic plasticity and synaptic homeostasis, long before inducing massive neuronal death. 54,55 Furthermore, ESCRT-III family protein, CHMP1A overexpression causes growth inhibition, chromatin condensation, and p53 phosphorylation ultimately leading to death in PANC-1 (pancreatic carcinoma of ductal origin from a Caucasian male) cells. 56 Another member of this family, CHMP1B interacts with the hereditary spastic paraplegia protein, spastin 57,58 ; suggesting that defects in this association may compromise intracellular membrane trafficking events.…”