Disease relevance of ntn1-A

• Netrin-1 and its receptors deleted in colorectal cancer (DCC) and neogenin are expressed within the developing visual system and have been implicated in mediating axon guidance and cell migration [1].

High impact information on ntn1-A

• These results support the model that cytoplasmic Ca2+ signals mediate growth-cone guidance by netrin-1, and different patterns of Ca2+ elevation trigger attractive and repulsive turning responses [2].
• The netrin-1-induced turning response depends on Ca2+ influx through plasma membrane Ca2+ channels, as well as Ca2+-induced Ca2+ release from cytoplasmic stores [2].
• Growth cones of retinal neurons exhibit chemoattractive turning towards the diffusible factor netrin-1 in vitro and are guided into the optic nerve head (ONH) by localized netrin-1 [3].
• Here we report that, in Xenopus, laminin-1 from the extracellular matrix (ECM), converts netrin-mediated attraction into repulsion [3].
• Here, we provide evidence that these two changes are causally linked: In the growth cones of embryonic Xenopus spinal axons, activation of the Slit receptor Roundabout (Robo) silences the attractive effect of netrin-1, but not its growth-stimulatory effect, through direct binding of the cytoplasmic domain of Robo to that of the netrin receptor DCC [4].

Biological context of ntn1-A

• Similar mutant phenotypes were also observed following loss of either RGMa or Netrin-1 [5].
• Pharmacological blockade of putative TRP currents or downregulation of Xenopus TRP-1 (xTRPC1) expression with a specific morpholino oligonucleotide abolished the growth-cone turning and Ca2+ elevation induced by a netrin-1 gradient [6].

Anatomical context of ntn1-A

• Age-related changes underlie switch in netrin-1 responsiveness as growth cones advance along visual pathway [7].
• Netrin-1-induced attraction was enhanced, and the repulsion induced by myelin-associated glycoprotein (MAG) or myelin membrane fragments was converted to attraction [8].
• Neogenin interacts with RGMa and Netrin-1 to guide axons within the embryonic vertebrate forebrain [5].

Associations of ntn1-A with chemical compounds

• Low levels of cyclic AMP in growth cones also lead to the conversion of netrin-induced attraction into repulsion, and we show that the amount of cAMP decreases in the presence of laminin-1 or YIGSR, suggesting a possible mechanism for laminin's effect [3].
• These findings show that netrin-1 responsiveness is developmentally regulated and suggest that intrinsic changes that lower cAMP levels underlie this regulation [7].
• Here we report that XTRPC1, a Xenopus homolog of mammalian TRPC1, is required for proper growth cone turning responses of Xenopus spinal neurons to microscopic gradients of netrin-1, brain-derived neurotrophic factor and myelin-associated glycoprotein, but not to semaphorin 3A [9].
• Disruption of lipid rafts by various approaches targeting cholesterol or gangliosides selectively abolished growth cone attraction and repulsion in BDNF and netrin-1 gradients, respectively, without affecting glutamate-induced attraction [10].
• Furthermore, cGMP signalling activated by an arachidonate 12-lipoxygenase metabolite suppresses LCC activity triggered by netrin-1, and is required for growth-cone repulsion mediated by the DCC-UNC5 receptor complex [11].

Other interactions of ntn1-A

• Here, we report that TRP-like channel activity exists in the growth cones of cultured Xenopus neurons and can be modulated by exposure to netrin-1 and brain-derived neurotrophic factor, two chemoattractants for axon guidance [6].

Analytical, diagnostic and therapeutic context of ntn1-A

• Whole-cell recording from growth cones showed that netrin-1 induced a membrane depolarization, part of which remained after all major voltage-dependent channels were blocked [6].

References