RESUMEN
The anterior commissure is the most ancient of the forebrain interhemispheric connections among all vertebrates. Indeed, it is the predominant pallial commissure in all non-eutherian vertebrates, universally subserving basic functions related to olfaction and survival. A key feature of the anterior commissure is its ability to convey connections from diverse brain areas, such as most of the neocortex in non-eutherian mammals, thereby mediating the bilateral integration of diverse functions. Shared developmental mechanisms between the anterior commissure and more evolutionarily recent commissures, such as the corpus callosum in eutherians, have led to the hypothesis that the former may have been a precursor for additional expansion of commissural circuits. However, differences between the formation of the anterior commissure and other telencephalic commissures suggest that independent developmental mechanisms underlie the emergence of these connections in extant species. Here, we review the developmental mechanisms and connectivity of the anterior commissure across evolutionarily distant species, and highlight its potential functional importance in humans, both in the course of normal neurodevelopment, and as a site of plastic axonal rerouting in the absence or damage of other connections.
Asunto(s)
Comisura Anterior Cerebral/crecimiento & desarrollo , Cuerpo Calloso/crecimiento & desarrollo , HumanosRESUMEN
Linx is a member of the leucine-rich repeat and immunoglobulin family of membrane proteins which has critical roles in the development of the peripheral nervous system and forebrain connectivity. A previous study showed that Linx is expressed in projection neurons in the cortex and in cells that comprise the passage to the prethalamus that form the internal capsule, indicating the involvement of Linx in axon guidance and cell-cell communication. In this study, we found that Linx-deficient mice develop severe hydrocephalus and die perinatally by unknown mechanisms. Importantly, mice heterozygous for the linx gene exhibited defects in the development of the anterior commissure in addition to hydrocephalus, indicating haploinsufficiency of the linx gene in forebrain development. In N1E-115 neuroblastoma cells and primary cultured hippocampal neurons, Linx depletion led to impaired neurite extension and an increase in cell body size. Consistent with this, but of unknown significance, we found that Linx interacts with and upregulates the activity of Rho-kinase, a modulator of many cellular processes including cytoskeletal organization. These data suggest a role for Linx in the regulation of complex forebrain connectivity, and future identification of its extracellular ligand(s) will help clarify this function.
Asunto(s)
Comisura Anterior Cerebral/crecimiento & desarrollo , Proteínas del Tejido Nervioso/genética , Sistema Nervioso Periférico/crecimiento & desarrollo , Prosencéfalo/crecimiento & desarrollo , Animales , Comisura Anterior Cerebral/metabolismo , Orientación del Axón/genética , Axones/metabolismo , Regulación del Desarrollo de la Expresión Génica , Hipocampo/crecimiento & desarrollo , Hipocampo/metabolismo , Sistema Límbico/crecimiento & desarrollo , Sistema Límbico/metabolismo , Proteínas de la Membrana/genética , Ratones , Neuronas/metabolismo , Sistema Nervioso Periférico/metabolismo , Prosencéfalo/metabolismoRESUMEN
Oligodendrocyte and myelin deficits have been reported in mental/psychiatric diseases. The p21-activated kinase 3 (PAK3), a serine/threonine kinase, whose activity is stimulated by the binding of active Rac and Cdc42 GTPases is affected in these pathologies. Indeed, many mutations of Pak3 gene have been described in non-syndromic intellectual disability diseases. Pak3 is expressed mainly in the brain where its role has been investigated in neurons but not in glial cells. Here, we showed that PAK3 is highly expressed in oligodendrocyte precursors (OPCs) and its expression decreases in mature oligodendrocytes. In the developing white matter of the Pak3 knockout mice, we found defects of oligodendrocyte differentiation in the corpus callosum and to a lesser extent in the anterior commissure, which were compensated at the adult stage. In vitro experiments in OPC cultures, derived from Pak3 knockout and wild type brains, support a developmental and cell-autonomous role for PAK3 in regulating OPC differentiation into mature oligodendrocytes. Moreover, we did not detect any obvious alterations of the proliferation or migration of Pak3 null OPCs compared to wild type. Overall, our data highlight PAK3 as a new regulator of OPC differentiation.