F3/Contactin acts as a modulator of neurogenesis during cerebral cortex development

Abstract

The expression of the cell recognition molecule F3/Contactin (CNTN1) is generally associated with the functions of post-mitotic neurons. In the embryonic cortex, however, we find it expressed by proliferating ventricular zone (VZ) precursors. In contrast to previous findings in the developing cerebellum, F3/Contactin transgenic overexpression in the early cortical VZ promotes proliferation and expands the precursor pool at the expense of neurogenesis. At later stages, when F3/Contactin levels subside, however, neurogenesis resumes, suggesting that F3/Contactin expression in the VZ is inversely related to neurogenesis and plays a role in a feedback control mechanism, regulating the orderly progression of cortical development. The modified F3/Contactin profile therefore results in delayed corticogenesis, as judged by downregulation in upper and lower layer marker expression and by BrdU birth dating, indicating that, in this transgenic model, increased F3/Contactin levels counteract neuronal precursor commitment. These effects also occur in primary cultures and are reproduced by addition of an F3/Fc fusion protein to wild type cultures. Together, these data indicate a completely novel function for F3/Contactin. Parallel changes in the generation of the Notch Intracellular Domain and in the expression of the Hes-1 transcription factor indicate that activation of the Notch pathway plays a role in this phenotype, consistent with previous in vitro reports that F3/Contactin is a Notch1 ligand.

The role of Gpi-anchored axonal glycoproteins in neural development and neurological disorders

“…In turn, such changes may reproduce the phenotype of specific neurological disorders, either inflammatory or degenerative in nature, consistent with the existence of a behavioural phenotype, indicative of changes in the cerebellar function in TAG/F3 mice (Coluccia et al, 2004). These disorders may correlate with signalling pathways activation, which, in the case of Contactin 1, may concern either Notch or pCREB factors-associated pathways (Hu et al, 2003;Bizzoca et al, 2012;Puzzo et al, 2013), known to affect neural precursor proliferation/differentiation events and to be involved in either neurodegenerative or neuroinflammatory (Dragunow, 2004;Shen, 2014;Pozueta et al, 2013;Wei et al, 2011) disorders.…”

“…Since the promoter element used in the TAG/F3 mice recapitulates a substantial part of normal CNTN2 expression, ectopic expression of CNTN1 is not limited to the cerebellum (Bizzoca et al, 2003;Bizzoca et al, 2012;Puzzo et al, 2013). In contrast to results from the cerebellum, in the early developing cerebral cortex, ectopic CNTN1 expression from the Cntn2 regulatory region -known to be expressed in cortical neural progenitors (see above) -was found…”

“…This appears to take the form either of Contactins being markers on mature cells that are detected by precursors as feedback signals to trigger or inhibit differentiation (Bizzoca et al, 2003;Xenaki et al, 2011), or that the Contactins are themselves present in the proliferating precursors as part of the apparatus modulating precursor behaviour (Ma et al, 2008;Bizzoca et al, 2012;Okamoto et al, 2013).…”

Development of the cerebellum: simple steps to make a ‘little brain’

“…4). Likewise, in contrast to its role in the cortical ventricular zone (Bizzoca et al, 2012), the lamina-specific expression of F3/contactin in the EGL suppresses Shh-dependent proliferation and is antagonised by its binding partner Tag1 (Xenaki et al, 2011), the deletion of which leads to ectopic subpial granule cell clusters in adult mice. Correspondingly, premature misexpression of F3/contactin attenuates granule cell progenitor proliferation (Bizzoca et al, 2003).…”

Neural Cell Adhesion Protein CNTN1 Promotes the Metastatic Progression of Prostate Cancer

“…Nevertheless, to the best of our knowledge, the role of CNTN1 in prostate cancer progression and metastasis is unknown. CNTN1 is a neural cell adhesion protein consisting of 6 N-terminal Ig domains followed by 4 fibronectin (FN)-like repeats (15) and plays important roles in the development of the central nervous system, including lineage commitment and precursor proliferation (16,17). CNTN1 also promotes axon elongation in the cerebellum, the formation of the septate-like junctions between axons and myelinating glial cells and the formation of the neuromuscular junction (5,18,19).…”