NRXN1
Neurexin-1-beta precursor (Neurexin I-beta)
Publications[править]
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.
MeSH Terms
- Aging
- Calcium-Binding Proteins
- Cell Adhesion Molecules, Neuronal
- Cerebral Cortex
- Embryonic Development
- Female
- Gene Expression Regulation, Developmental
- Humans
- Infant
- Male
- Nerve Tissue Proteins
- Neural Cell Adhesion Molecules
- Neurogenesis
- Tissue Distribution
Keywords
- cortical development
- neurexins
- neurodevelopmental disorders
- subplate
Neurexin 1 ([[NRXN1]]), a presynaptic cell adhesion molecule, is implicated in several neurodevelopmental disorders characterized by synaptic dysfunction including autism, intellectual disability and schizophrenia. To gain insight into [[NRXN1]]'s involvement in human cortical development we used quantitative real-time PCR to examine the expression trajectories of [[NRXN1]], and its predominant isoforms, [[NRXN1]]-α and [[NRXN1]]-β, in prefrontal cortex from fetal stages to aging. In addition, we investigated whether prefrontal cortical expression levels of [[NRXN1]] transcripts are altered in schizophrenia or bipolar disorder in comparison with non-psychiatric control subjects. We observed that all three [[NRXN1]] transcripts were highly expressed during human fetal cortical development, markedly increasing with gestational age. In the postnatal dorsolateral prefrontal cortex, expression levels were negatively correlated with age, peaking at birth until ~3 years of age, after which levels declined markedly to be stable across the lifespan. [[NRXN1]]-β expression was modestly but significantly elevated in the brains of patients with schizophrenia compared with non-psychiatric controls, whereas [[NRXN1]]-α expression was increased in bipolar disorder. These data provide novel evidence that [[NRXN1]] expression is highest in human dorsolateral prefrontal cortex during critical developmental windows relevant to the onset and diagnosis of a range of neurodevelopmental disorders, and that [[NRXN1]] expression may be differentially altered in neuropsychiatric disorders.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Aging
- Bipolar Disorder
- Calcium-Binding Proteins
- Cell Adhesion Molecules, Neuronal
- Child
- Child, Preschool
- Female
- Humans
- Infant
- Infant, Newborn
- Male
- Middle Aged
- Neocortex
- Nerve Tissue Proteins
- Neural Cell Adhesion Molecules
- Protein Isoforms
- Schizophrenia
- Young Adult