Neurexins 1–3 Each Have a Distinct Pattern of Expression in the Early Developing Human Cerebral Cortex

Abstract

Neurexins (NRXNs) are presynaptic terminal proteins and candidate neurodevelopmental disorder susceptibility genes; mutations presumably upset synaptic stabilization and function. However, analysis of human cortical tissue samples by RNAseq and quantitative real-time PCR at 8–12 postconceptional weeks, prior to extensive synapse formation, showed expression of all three NRXNs as well as several potential binding partners. However, the levels of expression were not identical; NRXN1 increased with age and NRXN2 levels were consistently higher than for NRXN3. Immunohistochemistry for each NRXN also revealed different expression patterns at this stage of development. NRXN1 and NRXN3 immunoreactivity was generally strongest in the cortical plate and increased in the ventricular zone with age, but was weak in the synaptogenic presubplate (pSP) and marginal zone. On the other hand, NRXN2 colocalized with synaptophysin in neurites of the pSP, but especially with GAP43 and CASK in growing axons of the intermediate zone. Alternative splicing modifies the role of NRXNs and we found evidence by RNAseq for exon skipping at splice site 4 and concomitant expression of KHDBRS proteins which control this splicing. NRXN2 may play a part in early cortical synaptogenesis, but NRXNs could have diverse roles in development including axon guidance, and intercellular communication between proliferating cells and/or migrating neurons.

Sublaminar organization of the human subplate: developmental changes in the distribution of neurons, glia, growing axons and extracellular matrix

“…() and Harkin et al. (). Experimental studies have also shown that the distribution of diverse SP neurons conforms to the multiple functional roles of SP (Kanold, ; Khazipov & Luhmann, ; Luhmann et al.…”

Neural substrate and clinical significance of general movements: an update

“…SVZ / VZ represents the subventricular and ventricular zones where the neurons and glial cells are generated; IM / PWM denotes the intermediate zone that gradually develops into the periventricular white matter; MZ is the marginal zone. The following three timelines represent from bottom to top: the hyperexcitability of the nervous system, in which the intensity of the grey shading represents the degree of hyperexcitability; the cortical network activity that emerges across the brain from 9 to 10 weeks PMA , this gradually increases (indicated by increasing shading) to be full‐blown present (in the subplate) at mid‐fetal age, before moving from global and widespread activity to local and limited activity (‘sparsification’, indicated by the diminution of the dots); on top the developmental changes in general movements. GM, general movements; PMA, postmenstrual age; CA, corrected age.…”

Smad4 signaling establishes the somatosensory map of basal vomeronasal sensory neurons

“…We propose that Smad4 mediated signaling may modulate the required gene expression and chromatin rearrangements to complete VSNs maturation. Proteins of the Nrxn1 family undergo dynamic expression as neurons mature during development (Harkin et al, 2017). Based on our findings in OMPCre +/-/Smad4 flox/flox (cKO) mutants, we speculate that changes in Nrx1 expression arise from an overall compromised maturation rather than a direct Smad4 dependent regulation.…”