Expression of the neurodevelopmental disease susceptibility genes CADM1 and CADM2 in the early human fetal forebrain

CADM1 and CADM2 are cell-adhesion molecules with likely roles in cell migration, axon guidance and synapse formation. Both are considered potential susceptibility genes for various neurodevelopmental disorders. However, their expression patterns in early human brain development have not been explored. Here we employed transcriptomics, RNAScope in situ hybridisation (ISH) and immunofluorescence (IF) to determine the time course and location of expression in the human cerebral cortex and thalamus between 7.5-17 postconceptional weeks (PCW). In the cerebral cortex, tissue RNAseq revealed both to be highly expressed throughout this period. CADM1 exhibited very high expression which declined slightly with age. CADM2 exhibited high expression which increased over time. Single-cell RNA-seq and ISH revealed that both genes were co-expressed in most cells; however, IF revealed different patterns of cellular localisation. At 8 PCW, expression for both CADMs was similar throughout the cortex and predominantly located in the cytoplasm/cell surface in the cortical plate (CP) but with stronger expression of CADM1 in the subventricular zone. However, from 10 PCW onwards, the strongest immunoreactivity for CADM1 was in the cell nucleus with weak cytoplasmic localisation, whereas CADM2 was expressed on the cell surface and increasingly in axons with age. By 17 PCW, CADM2 exhibited strong immunoreactivity in the thalamocortical and callosal corticocortical axons but was weakly expressed in corticofugal pathways. In the thalamus, CADM2 expression in posterior and lateral projection neurons contributing to thalamocortical pathways was confirmed. CADM1 and CADM2 show differential expression in the thalamus and associated nuclei, suggesting a role in their segregation; CADM1 favouring anterior and medial thalamic nuclei and the ventromedial subthalamus, CADM2 the lateral habenula, lateral and posterior thalamus and dorsolateral subthalamus. CADM1 and CADM2 may play important and varied roles in early fetal human forebrain development, guiding cell migration and aggregation, and axon guidance and fasciculation.