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.
Highlights
Linx, termed Immunoglobulin Superfamily Containing Leucine-rich Repeat 2 (Islr2), is a type I transmembrane protein and a member of the LIG family of proteins with five tandem LRRs, an Ig-like domain, a transmembrane domain, and an intracellular domain, and that is expressed in neural tissues (Fig. 1A)[4,5]
Given the interaction of Linx with Ret and many previous studies showing that Lrig[1,2,3], other members of the LIG family, interact with epidermal growth factor receptor (EGFR) to regulate embryonic development and cancer progression[4,18,19], we initially hypothesized that Linx could be a critical regulator of Ret function
Linx expression was abundant in the cerebrum and the olfactory bulb (OB) but not in the cerebellum nor spinal cord, indicating a role for Linx in the function or development of the forebrain (Fig. 1D)
Summary
Termed Immunoglobulin Superfamily Containing Leucine-rich Repeat 2 (Islr2), is a type I transmembrane protein and a member of the LIG family of proteins with five tandem LRRs, an Ig-like domain, a transmembrane domain, and an intracellular domain, and that is expressed in neural tissues (Fig. 1A)[4,5]. It has been reported that Linx binds to RTKs including TrkA and Ret, receptors for nerve growth factor (NGF) and glial-derived neurotrophic factor (GDNF), respectively, to modulate the intensity of their signaling cascades, their precise binding selectivity and modes of interaction have yet to be fully elucidated[4]. Defects in axonal intermingling between thalamocortical and corticofugal neurons and the formation of the internal capsule (IC) were observed in the forebrain of Linx-deficient mice[12]. This phenotype was not fully explained by the impaired action of NGF and GDNF, suggesting that Linx interacts with other unknown ligand(s) to exert its biological functions. We identified Rho-kinase as an interacting protein with Linx, further suggesting the involvement of Linx in cytoskeletal organization and other various cellular processes during brain development
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