Essential Role of Linx/Islr2 in the Development of the Forebrain Anterior Commissure

Abstract

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.

Pathological priming causes developmental gene network heterochronicity in autistic subject-derived neurons

“…7c), suggesting a subtle primed state of the neuronal network program in ASD NSCs. Among the top negatively correlated TM1 genes, the F-box protein 2 ( FBXO2) gene is involved in regulating the postmitotic neuronal state and the initiation of synapse formation 27,28 , whereas other genes encoding for the small GTP-binding protein RASD2 or the transmembrane protein ISLR2 have been implicated in schizophrenia 29 or have important functions in neurite extension and regulating forebrain connectivity 30,31 (Extended Data Fig. 7d-h).…”

A Human IgSF Cell-Surface Interactome Reveals a Complex Network of Protein-Protein Interactions

“…In our screen, one or more DCC subfamily members also bound to: (1) WFIKKN2, a secreted protein that binds transforming growth factor-beta subfamily members and modulates their presentation to cells ( Monestier and Blanquet, 2016 ), (2) lactotransferrin (LTF), an iron-binding protein with antimicrobial activity ( Hao et al., 2019 ), (3) interleukin-6 receptor subunit alpha (IL-6Rα), a cytokine receptor ( Schaper and Rose-John, 2015 ), and (4) ISLR2/LINX, which functions in nervous system development ( Mandai et al., 2014 ; Panza et al., 2015 ; Abudureyimu et al., 2018 ). We confirmed binding of all DCC subfamily members to these proteins by SPR and to other proteins observed in our screen ( Figures 3 C, 3D, and 3F).…”

Novel genome-wide associations for anhedonia, genetic correlation with psychiatric disorders, and polygenic association with brain structure

“…ISLR2 on chromosome 15 is involved in neurodevelopment 59 but its role in psychiatric and neurological traits is not well characterised. Another candidate gene within this locus, NRG4 , encodes a neuregulin protein that activates type-1 growth factor receptors.…”