Soluble adenylyl cyclase is not required for axon guidance to netrin-1.
During development, axons are directed to their targets by extracellular guidance cues. The axonal response to the guidance cue netrin-1 is profoundly influenced by the concentration of cAMP within the growth cone. In some cases, cAMP affects the sensitivity of the growth cone to netrin-1, whereas in others it changes the response to netrin-1 from attraction to repulsion. The effects of cAMP on netrin-1 action are well accepted, but the critical issue of whether cAMP production is activated by a netrin-1 induced signaling cascade remains uncertain. A previous report has suggested that axon guidance in response to netrin-1 requires cAMP production mediated by soluble adenyl cyclase (sAC). We have used genetic, molecular and biochemical strategies to assess this issue. Surprisingly, we found only extremely weak expression of sAC in embryonic neurons and determined that, under conditions where netrin-1 directs axonal pathfinding, exposure to netrin-1 does not alter cAMP levels. Furthermore, although netrin-1-deficient mice exhibit major axon guidance defects, we show that pathfinding is normal in sAC-null mice. Therefore, although cAMP can alter the response of axons to netrin-1, we conclude that netrin-1 does not alter cAMP levels in axons attracted by this cue, and that sAC is not required for axon attraction to netrin-1.
Moore
Simon W
SW
Centre for Neuronal Survival, Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada H3A 2B4.
Lai Wing Sun
Karen
K
Xie
Fang
F
Barker
Philip A
PA
Conti
Marco
M
Kennedy
Timothy E
TE
D000262:Adenylyl Cyclases / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000502:physiology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism / Q000502:physiology; D004622:Embryo, Mammalian / Q000378:metabolism / Q000502:physiology; D005727:Ganglia, Spinal / Q000166:cytology / Q000196:embryology; D020439:Growth Cones / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000494:pharmacology*; D000075388:Netrin-1; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D012995:Solubility; D025521:Tumor Suppressor Proteins / Q000494:pharmacology*
C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; C000617354:Ntn1 protein, rat; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; D000242:Cyclic AMP; D000262:Adenylyl Cyclases