Regulation of TrkA and ChAT expression in developing rat basal forebrain: evidence that both exogenous and endogenous NGF regulate differentiation of cholinergic neurons.
TrkA is a receptor tyrosine kinase whose activation transduces NGF signaling. TrkA expression has been demonstrated in NGF-responsive adult basal forebrain cholinergic neurons (BFCNs). Several lines of evidence have suggested that endogenous NGF plays a role in the development and differentiation of these neurons. We examined TrkA expression during development. TrkA mRNA and protein were present in basal forebrain neurons during the entire postnatal period; the distribution of neurons bearing these markers was identical to that for those containing choline acetyltransferase (ChAT) mRNA, suggesting that, as in the adult, TrkA gene expression is localized to BFCNs. The expression of TrkA and ChAT followed a very similar temporal pattern, suggesting regulation by the same factor(s). We discovered that NGF administration in vivo activated TrkA receptors, and increased both TrkA and ChAT mRNA; conversely, anti-NGF infusions suppressed expression of both genes. These results suggest that endogenous NGF regulates expression of TrkA and ChAT. Finally, while NGF infusion increased the size of developing BFCNs, NGF antibodies inhibited the normal developmental increase. The results are evidence that endogenous NGF acts on developing BFCNs to enhance gene expression and cellular differentiation.
Li
Y
Y
Department of Neurology, University of California at San Francisco 94143, USA.
Holtzman
D M
DM
Kromer
L F
LF
Kaplan
D R
DR
Chua-Couzens
J
J
Clary
D O
DO
Knüsel
B
B
Mobley
W C
WC
D000375:Aging / Q000378:metabolism*; D000818:Animals; D015152:Blotting, Northern; D002795:Choline O-Acetyltransferase / Q000096:biosynthesis*; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D009414:Nerve Growth Factors / Q000494:pharmacology; D019000:Phosphotyrosine; D016548:Prosencephalon / Q000254:growth & development / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000378:metabolism; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis* / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; D019000:Phosphotyrosine; D014443:Tyrosine; D002795:Choline O-Acetyltransferase; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA