Netrins/UNC-6 (netr: Sanskrit for “one who guides”) are a family of laminin-related small proteins that are involved in neurite outgrowth and axon guidance. Netrins bind to the DCC and UNC5 family of receptors to attract or repel axons. Human Netrin-4 is synthesized as a 628 amino acid (aa) precursor that contains a 19 aa signal sequence, a 443 aa laminin-related region containing an N-terminal laminin globular domain (domain VI) followed by 3 laminin EGF-like repeats, and a 166 aa C‑terminal domain rich in basic residues that serves as a heparin binding site. Unlike human Netrin-1 which is reminiscent of the laminin gamma -chain, human Netrin-4 resembles the laminin beta -chain. Netrin-4 has been reported to exist as both a monomer and a dimer. The dimeric form was reported to be the less active of the two. Human Netrin-4 shares 31%, 29% and 25% aa sequence identity with human Netrin-1, 2 and G2, respectively; it shares 89% aa identity with mouse Netrin-4. Netrin-4 has widespread expression, occurring in nervous tissues such as embryonic floor plate and postnatal neurons such as cerebellar granule cells and hippocampal pyramidal cells. It also is found in non-neural tissues, such as adult Bowman’s capsule and medullary tubular epithelium in kidney, and embryonic pancreatic and intestinal epithelium, plus cells of the ureteric bud. Netrin-4 expression is often associated with basement membrane. Netrin-4 has been shown to initiate axon outgrowth from olfactory bulb explants (1‑7).
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