Contactin-1/F3 Regulates Neuronal Migration and Morphogenesis Through Modulating RhoA Activity

Abstract

During neocortical development, newborn neurons migrate along radial fibers from the germinal ventricular zone (VZ) toward the cortical plate (CP) to populate the cerebral cortex. This radial migration requires adhesion activities between neurons and radial fibers; however, past research has identified only a limited number of adhesion molecules involved in this process. Contactin-1/F3 (Cntn1), a cell adhesion molecule expressed in the developing nervous system is essential for many key developmental events including neural cell adhesion, neurite outgrowth, axon guidance and myelination. However, the potential role of Cntn1 in neuronal migration during cortical development has not been investigated. Here we used in utero electroporation to introduce short hairpin RNA (shRNA) to knock down (KD) Cntn1 in neural stem cells in vivo. We found that Cntn1 KD led to a delay in neuronal migration. The arrested cells presented abnormal morphology in their leading process and more multipolar cells were observed in the deep layers of the brain, suggestive of dysregulation in process formation. Intriguingly, Cntn1 KD also resulted in upregulation of RhoA, a negative regulator for neuronal migration. Interference of RhoA by expression of the dominant-negative RhoAN19 partially rescued the neuronal migration defects caused by Cntn1 KD. Our results showed that Cntn1 is a novel adhesion protein that is essential for neuronal migration and regulates process formation of newborn cortical neurons through modulating RhoA signaling pathway.

Impairment in dynein-mediated nuclear translocation by BICD2 C-terminal truncation leads to neuronal migration defect and human brain malformation

“…To directly monitor the effects of BicD2 K775X variant on neuronal migration, we employed time-lapse imaging of neurons in live embryonic brain slices [8,9,49]. Brains electroporated with BicD2 WT or K775X at E14.5 were sliced and cultured at E17.5.…”

“…The live brain slice imaging was performed as previous described [8,9,51]. Briefly, live mouse brains were coronal sectioned into 350 μm-thick slices using the Vibratome (Leica) 2.5 days after electroporation.…”

Molecular and Cellular Substrates for the Friedreich Ataxia. Significance of Contactin Expression and of Antioxidant Administration

“…In addition, due to the mentioned Contactins involvement in myelination [ 55 , 89 , 103 , 104 ], changes in their expression may also concern disorders of myelinated axons and therefore of nerve conduction velocities [ 105 ]. In this context, besides the described effects on the neuronal lineage, in the present study, specific consequences were also demonstrated on the glial lineage by using a glia-specific marker as the GFAP, whose expression underwent a significant increase in the course of the disorder, thus justifying that a glia upregulation accompanied the observed neuronal degenerative phenotype, confirming the simultaneous activation of a neurorepair mechanism [ 56 , 57 , 66 , 67 , 106 ].…”

Mutations of CNTNAP1 led to defects in neuronal development

“…These results indicate that Cntnap1 deficiency delays neuronal migration during perinatal cortical development. The binding of contactin to CNTNAP1 in cis interactions in the plasma membrane is required for developmental events such as neurite growth, neural cell adhesion, myelination, and neuronal migration (19,38,39). In Cntn1-KO mice, axonal guidance and dendritic projections in granule cells are defective (40).…”

“…CNTNAP1 is highly expressed in radial glial cells (RGCs) in the early neurogenic period and plays a decisive role in the timing of neuron and astrocyte generation (12). CNTNAP1 has also been found to bind Cntn1 (13,14), neurofascin (2,15,16), and native prion protein (17), which are involved in neurite outgrowth (18), neuronal migration (19), dendritic branching (20,21), and synaptogenesis (22), thereby allowing inferences about its potential functions in early brain development.…”