Cadherin-13 Deficiency Increases Dorsal Raphe 5-HT Neuron Density and Prefrontal Cortex Innervation in the Mouse Brain

Abstract

Background: During early prenatal stages of brain development, serotonin (5-HT)-specific neurons migrate through somal translocation to form the raphe nuclei and subsequently begin to project to their target regions. The rostral cluster of cells, comprising the median and dorsal raphe (DR), innervates anterior regions of the brain, including the prefrontal cortex. Differential analysis of the mouse 5-HT system transcriptome identified enrichment of cell adhesion molecules in 5-HT neurons of the DR. One of these molecules, cadherin-13 (Cdh13) has been shown to play a role in cell migration, axon pathfinding, and synaptogenesis. This study aimed to investigate the contribution of Cdh13 to the development of the murine brain 5-HT system.Methods: For detection of Cdh13 and components of the 5-HT system at different embryonic developmental stages of the mouse brain, we employed immunofluorescence protocols and imaging techniques, including epifluorescence, confocal and structured illumination microscopy. The consequence of CDH13 loss-of-function mutations on brain 5-HT system development was explored in a mouse model of Cdh13 deficiency.Results: Our data show that in murine embryonic brain Cdh13 is strongly expressed on 5-HT specific neurons of the DR and in radial glial cells (RGCs), which are critically involved in regulation of neuronal migration. We observed that 5-HT neurons are intertwined with these RGCs, suggesting that these neurons undergo RGC-guided migration. Cdh13 is present at points of intersection between these two cell types. Compared to wildtype controls, Cdh13-deficient mice display increased cell densities in the DR at embryonic stages E13.5, E17.5, and adulthood, and higher serotonergic innervation of the prefrontal cortex at E17.5.Conclusion: Our findings provide evidence for a role of CDH13 in the development of the serotonergic system in early embryonic stages. Specifically, we indicate that Cdh13 deficiency affects the cell density of the developing DR and the posterior innervation of the prefrontal cortex (PFC), and therefore might be involved in the migration, axonal outgrowth and terminal target finding of DR 5-HT neurons. Dysregulation of CDH13 expression may thus contribute to alterations in this system of neurotransmission, impacting cognitive function, which is frequently impaired in neurodevelopmental disorders including attention-deficit/hyperactivity and autism spectrum disorders.

LCM-seq identifies robust markers of vulnerable and resistant human midbrain dopamine neurons

“…Cdh13 encodes for adhesion protein 13, which together with other family members as Cdh9 and Cdh15 are linked to neuropsychiatric disorders (Redies et al 2012). Cdh13 can regulate neuronal migration and also has an effect on axonal outgrowth as demonstrated in the serotonergic system (Forero et al 2017). Zcchc12 on the other hand is a transcriptional co-activator that positively regulates BMP signaling through interaction with Smads and CBP, and appears necessary for basal forebrain cholinergic neuron gene expression (Cho et al 2008b).…”

Spatial RNA sequencing identifies robust markers of vulnerable and resistant human midbrain dopamine neurons and their expression in Parkinson’s Disease

“…Cdh15 is linked to neuropsychiatric disorders (Redies et al, 2012). Cdh13 can regulate neuronal migration and also has an effect on axonal outgrowth as demonstrated in the serotonergic system (Forero et al, 2017). Zcchc12 on the other hand is a transcriptional co-activator that positively regulates BMP signaling through interaction with Smads and CBP and appears necessary for basal forebrain cholinergic neuron gene expression (Cho et al, 2008b).…”

Weighted Single-Step Genome-Wide Association Study for Growth Traits in Chinese Simmental Beef Cattle

“…Notably, MYH10 gene has been highlighted as a strong candidate in the association analysis for YW and additional laboratory functional experiments would be needed. CDH13 gene encodes a member of the cadherin superfamily and acts as a negative regulator of axon growth during neural differentiation [38]. FOXP1 gene plays an important role in the regulation of tissue and cell type-specific gene transcription during both development and adulthood and controls adipocyte differentiation [39].…”