c-ret regulates cholinergic properties in mouse sympathetic neurons: evidence from mutant mice.
The search for signalling systems regulating development of noradrenergic and cholinergic sympathetic neurons is a classical problem of developmental neuroscience. While an essential role of bone morphogenetic proteins for induction of noradrenergic properties is firmly established, factors involved in the development of cholinergic traits in vivo are still enigmatic. Previous studies have shown that the c-ret receptor and cholinergic properties are coexpressed in chick sympathetic neurons. Using in situ hybridization we show now that a loss-of-function mutation of the c-ret receptor in mice dramatically reduces numbers of cells positive for choline acetyltransferase (ChAT) and the vesicular acetylcholine transporter (VAChT) in stellate ganglia of homozygous newborn animals. The number of neurons positive for tyrosine hydroxylase (TH) mRNA, the rate-limiting enzyme of noradrenaline synthesis, is reduced to a smaller degree and expression levels are not detectably altered. Already at embryonic day 16 (E16), ChAT and VAChT-positive cells are affected by the c-ret mutation. At E14, however, ChAT and VAChT mRNAs are detectable at low levels and no difference is observed between wildtype and mutant mice. Our data suggest that c-ret signalling is necessary for the maturation of cholinergic sympathetic neurons but dispensable for de novo induction of ChAT and VAChT expression.
Burau
K
K
Interdisciplinary Center for Neurosciences, Department of Neuroanatomy, University of Heidelberg, INF 307, D-69120 Heidelberg, Germany.
Stenull
I
I
Huber
K
K
Misawa
H
H
Berse
B
B
Unsicker
K
K
Ernsberger
U
U
D000109:Acetylcholine / Q000378:metabolism*; D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002452:Cell Count / Q000379:methods; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009474:Neurons / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D013233:Stellate Ganglion / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000166:cytology* / Q000196:embryology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins / Q000378:metabolism
D026901:Membrane Transport Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C493460:Slc18a3 protein, mouse; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins; D014446:Tyrosine 3-Monooxygenase; D002795:Choline O-Acetyltransferase; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C494999:Ret protein, mouse; D000109:Acetylcholine