Slitrks as emerging candidate genes involved in neuropsychiatric disorders

Abstract

Slitrks are a family of structurally-related transmembrane proteins belonging to the leucine-rich repeat (LRR) superfamily. Six family members exist (Slitrk1-Slitrk6), and all are highly expressed in the central nervous system (CNS). Slitrks have been implicated in mediating basic neuronal processes ranging from neurite outgrowth and dendritic elaboration to neuronal survival. Recent studies in humans and genetic mouse models have led to the identification of Slitrks as candidate genes that may be involved in the development of neuropsychiatric conditions such as obsessive compulsive spectrum disorders and schizophrenia. While these system level approaches have suggested that Slitrks play prominent roles in CNS development, key questions remain regarding the molecular mechanisms through which Slitrks mediate neuronal signaling and connectivity. SLITRK FAMILYThe Slitrk gene family is composed of six members (Slitrk1 -Slitrk6), which are highly expressed in the central nervous system (CNS) [1,2]. This family was identified in a screen for genes that were differentially expressed in mice with neural tube defects [1]. Slitrk5 had been previously discovered as a gene expressed in early hematopoietic progenitors but not in mature hematopoietic cells [3]. All Slitrks form single pass (type I) transmembrane proteins with an intracellular domain that varies in length [1]. At the extracellular domain, Slitrks contain two leucine-rich repeat (LRR) domains, which are each composed of 13 to 17 LRRs, flanked by cysteine rich domains (Glossary) [1]. Sequence analysis has revealed that the © 2011 Elsevier Ltd. All rights reserved. +Corresponding Authors: ccp2001@med.cornell.edu and fslee@med.cornell.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflict of interest statementThe authors declare no competing financial interests. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript extracellular LRR domains of Slitrks resembled Slit proteins, and a conserved region in their intracellular carboxyl terminus (C-terminus) has a high degree of consensus with the last 16 amino acids of the neurotrophin receptor, tropomyosin-related kinase (Trk) [1]. Based on their similarity with Slits and Trks, these proteins were named Slitrks [1].Slitrks are classified as members of the LRR superfamily, due to the presence of the LRR domains. The LRR superfamily is a class of molecules containing structural motifs of 20-29 amino acids with a defining sequence LxxLxLxxN/GxL (x being any amino acid) [4,5]. LRR domains are composed of tandem repeats of this L...

Slitrks control excitatory and inhibitory synapse formation with LAR receptor protein tyrosine phosphatases

“…Recently, Slitrk3 was shown to control inhibitory synapse development selectively (13). Despite this progress, little about the synaptic functions of other Slitrk isoforms, apart from their ability to regulate neurite outgrowth (14), has been studied in detail.…”

Lmx1a and Lmx1b regulate mitochondrial functions and survival of adult midbrain dopaminergic neurons

“…Although the function of these genes in mDA neurons remains unknown, these proteins have been shown to affect neurite outgrowth (27) and are involved in the formation of regulation synapses (28). Human genetic studies also have linked rare mutations in SLITRK genes with obsessive-compulsive spectrum disorders and other neuropsychiatric disorders including attention deficit hyperactivity disorder (29). A change in the expression of genes important for the correct wiring or for the synaptogenesis of mDA neurons could indeed have diverse consequences on behavior (including hyperactivity), but further studies would be required to confirm this hypothesis.…”

SLITRK6 mutations cause myopia and deafness in humans and mice

“…In the current study, we showed that mutation of SLITRK6 results in a human syndrome that includes high myopia and sensorineural deafness as the only clinical findings and confirmed a similar phenotype in Slitrk6 mutant mice. SLITRK gene family members are highly expressed in both human and murine central nervous systems (20,21) and are currently considered emerging candidate genes for neuropsychiatric disorders (29). The family consist of 6 structurally related transmembrane proteins belonging to the LRR superfamily and are single-pass (type 1) transmembrane proteins highly expressed in the central nervous system (23).…”