Trans-induced cis interaction in the tripartite NGL-1, netrin-G1, and LAR adhesion complex promotes excitatory synaptic development

Abstract

SummaryThe initial contact between axons and dendrites at early neuronal synapses is mediated by surface adhesion molecules and is thought to induce synaptic maturation through the recruitment of additional synaptic proteins. The initiation of synaptic maturation should be tightly regulated to ensure that synaptic maturation occurs selectively at subcellular sites of axo-dendritic adhesion. However, the underlying mechanism is poorly understood. Here, we report that the initial trans-synaptic adhesion mediated by presynaptic netrin-G1 and postsynaptic NGL-1 (netrin-G1 ligand-1) induces a cis interaction between netrin-G1 and the receptor protein tyrosine phosphatase LAR (leukocyte antigen-related), and that this promotes presynaptic differentiation. We propose that trans-synaptic adhesions at early neuronal synapses trigger recruitment of neighboring adhesion molecules in a cis manner in order to couple initial axo-dendritic adhesion with synaptic differentiation.

Netrin G1 promotes pancreatic tumorigenesis through cancer associated fibroblast driven nutritional support and immunosuppression

“…In this study we sought to clarify the roles of CAFs in PDAC tumorigenesis. We uncovered upregulation of the glutamatergic pre-synaptic protein, Netrin G1 (NetG1) (Nakashiba et al, 2000;Song et al, 2013), in CAFs. Surprisingly, we also found up-regulation of Netrin G1 Ligand (NGL-1), the post-synaptic binding partner of NetG1 (Lin et al, 2003) in PDAC cells, and that both NetG1 and NGL-1 were overexpressed in PDAC human tissue compared to samples from normal human pancreas.…”

Control of neural circuit formation by leucine-rich repeat proteins

“…Decreased expression of specific NTNG1 splice variants has also been observed in patients with schizophrenia and bipolar disorder [87, 88]. This could conceivably affect binding of Netrin-G1 to LAR, which is modulated by alternative splicing of Netrin-G1 [43], and thus perturb synapse development. Rare missense mutations in NTNG1 and LRRTM1 (Table 1) do not seem to affect critical regions of the proteins.…”

“…The lack of a cytoplasmic domain in Netrin-Gs suggests the existence of a transmembrane co-receptor to mediate NGL-1- and NGL-2-induced presynaptic differentiation. Indeed, NGL-1 binding to presynaptic Netrin-G1 induces a cis interaction of Netrin-G1 with LAR to promote presynaptic differentiation [43]. Netrin-G1 binding to LAR is modulated by alternative splicing of Netrin-G1 [43], which can generate at least 10 isoforms [44–46].…”

“…Indeed, NGL-1 binding to presynaptic Netrin-G1 induces a cis interaction of Netrin-G1 with LAR to promote presynaptic differentiation [43]. Netrin-G1 binding to LAR is modulated by alternative splicing of Netrin-G1 [43], which can generate at least 10 isoforms [44–46]. Alternative splicing of Netrin-G2 does not affect binding to NGL-2 [47], suggesting that Netrin-G splicing serves to regulate cis interactions.…”

“…One possibility could be that through alternative splicing, Netrin-Gs may couple trans-synaptic interaction with NGLs to a network of multiple cis receptors, providing additional layers of control over synapse development. Remarkably, NGL-2 binding to Netrin-G2 does not recruit LAR to the complex [43], suggesting the existence of additional cis interactors. Whether these are other RPTPs or unrelated synaptic receptors remains to be determined.…”