Developmental role of the cell adhesion molecule Contactin-6 in the cerebral cortex and hippocampus

Abstract

The gene encoding the neural cell adhesion molecule Contactin-6 (Cntn6 a.k.a. NB-3) has been implicated as an autism risk gene, suggesting that its mutation is deleterious to brain development. Due to its GPI-anchor at Cntn6 may exert cell adhesion/receptor functions in complex with other membrane proteins, or serve as a ligand. We aimed to uncover novel phenotypes related to Cntn6 functions during development in the cerebral cortex of adult Cntn6 ¡/¡ mice. We first determined Cntn6 protein and mRNA expression in the cortex, thalamic nuclei and the hippocampus at P14, which decreased specifically in the cortex at adult stages. Neuroanatomical analysis demonstrated a significant decrease of Cux1C projection neurons in layers II-IV and an increase of FoxP2C projection neurons in layer VI in the visual cortex of adult Cntn6 ¡/¡ mice compared to wild-type controls. Furthermore, the number of parvalbuminC (PV) interneurons was decreased in Cntn6 ¡/¡ mice, while the amount of NPYC interneurons remained unchanged. In the hippocampus the delineation and outgrowth of mossy fibers remained largely unchanged, except for the observation of a larger suprapyramidal bundle. The observed abnormalities in the cerebral cortex and hippocampus of Cntn6 ¡/¡ mice suggests that Cntn6 serves developmental functions involving cell survival, migration and fasciculation. Furthermore, these data suggest that Cntn6 engages in both trans-and cis-interactions and may be involved in larger protein interaction networks.

Association of Cell Adhesion Molecules Contactin-6 and Latrophilin-1 Regulates Neuronal Apoptosis

“…Current insights in the mode of action of Cntn6 were too limited to fully explain its involvement in developmental mechanisms, despite the description of phenotypes in null mutant mice, such as biochemical interactors (Zuko et al, 2013). These phenotypes included a developmental delay of the corticospinal tract, a misorientation of apical dendrites in the cortex, altered numbers of subtype specific projection neurons and interneurons in the cortex, and an increase in neuronal cell death during cerebellar development (Ye et al, 2008; Sakurai et al, 2009; Pinto et al, 2010; Huang et al, 2011b; Zuko et al, 2016). Also, significant reduction in glutamatergic synapses was found in the hippocampus and in the cerebellum of Cntn6 null-mutants (Sakurai et al, 2009, 2010).…”

Cntn6 deficiency impairs allocentric navigation in mice

“…The hippocampal structure plays an important role in spatial learning and memory. It has been reported that the length and area size of the suprapyramidal bundle (SPB) in the hippocampus were significantly increased in Cntn6 −/− mice (Zuko et al., ). Here, we examined whether Cntn6 deficiency affected hippocampus‐related behavior in the Morris water maze task.…”

“…Amila Zuko et al. found that Cntn6 deficiency in the dentate gyrus (DG) may impair the fasciculation of mossy fibers that innervate pyramidal cells in the hippocampus (Cremer, Chazal, Goridis, & Represa, ; Heyden, Angenstein, Sallaz, Seidenbecher, & Montag, ; Montag‐Sallaz, Schachner, & Montag, ; Zuko et al., ). Some studies showed that F3/Contactin, another member of the contactin family, promotes hippocampal neurogenesis in adult mice (Mercati et al., ; Puzzo et al., ; Sakurai et al., , ).…”

“…In the hippocampus, a significant reduction in glutamatergic synapses was found in the Cntn6-deficient mice in the postnatal stage (Sakurai, Toyoshima, Takeda, Shimoda, & Watanabe, 2010;Sakurai et al, 2009). Amila Zuko et al found that Cntn6 deficiency in the dentate gyrus (DG) may impair the fasciculation of mossy fibers that innervate pyramidal cells in the hippocampus (Cremer, Chazal, Goridis, & Represa, 1997;Heyden, Angenstein, Sallaz, Seidenbecher, & Montag, 2008;Montag-Sallaz, Schachner, & Montag, 2002;Zuko et al, 2016). Some studies showed that F3/Contactin, another member of the contactin family, promotes hippocampal neurogenesis in adult mice (Mercati et al, 2017;Puzzo et al, 2013;Sakurai et al, 2009Sakurai et al, , 2010.…”

Genome‐wide association study of HIV‐associated neurocognitive disorder (HAND): A CHARTER group study

“…ANAPC13 functions in the ubiquitin-mediated proteolysis pathway. CNTN6 encodes a neural adhesion molecule which has been associated with intellectual disability [Kashevarova and others 2014] in children, and copy number variants in this gene have recently been identified it as a candidate for a wide spectrum of neurobehavioral disorders [Hu and others 2015]; this gene may also function in a large number of protein interaction networks important for normal brain development [Zuko and others 2016]. The gene CSMD1 has been associated with sporadic Alzheimer’s disease [Parcerisas and others 2014], schizophrenia [Koiliari and others 2014], cannabis dependence [Koiliari and others 2014], and other neuropsychiatric disorders.…”