Cooperative effects of Sonic Hedgehog and NGF on basal forebrain cholinergic neurons.
In ventromedial cells of the developing CNS, Sonic hedgehog (Shh) has been shown to affect precursor proliferation, phenotype determination, and survival. Here we show that Shh and its receptor, Ptc-1, are expressed in the adult rat basal forebrain, and that Ptc-1 is expressed specifically by cholinergic neurons. In basal forebrain cultures, Shh was added alone and in combination with nerve growth factor (NGF), and the number of cholinergic neurons was determined by choline acetyltransferase (ChAT) immunocytochemistry. By 8 days in vitro, Shh and NGF show a synergistic effect: the number of ChAT-positive cells after treatment with both factors is increased over untreated cultures or cultures treated with either factor alone. While Shh increases the overall basal level of proliferation, double-labeling of dividing neuronal precursors with [(3)H]thymidine followed by ChAT immunocytochemistry after they mature, demonstrates that the specific increase in cholinergic neurons is not due to this proliferation enhancement. These experiments imply a role for Shh in the development of postmitotic cholinergic neurons and suggest a therapeutic value for Shh in neurodegenerative disease.
Reilly
Jennifer Ott
JO
Curis, Incorporated, 61 Moulton Street, Cambridge, Massachusetts 02138, USA.
Karavanova
Irina D
ID
Williams
Kevin P
KP
Mahanthappa
Nagesh K
NK
Allendoerfer
Karen L
KL
D000109:Acetylcholine / Q000502:physiology; D000367:Age Factors; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002795:Choline O-Acetyltransferase / Q000032:analysis; D004357:Drug Synergism; D015870:Gene Expression / Q000502:physiology; D053823:Hedgehog Proteins; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D016548:Prosencephalon / Q000166:cytology; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface; D015534:Trans-Activators / Q000235:genetics / Q000494:pharmacology*
D053823:Hedgehog Proteins; D008565:Membrane Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; C000606239:Ptch1 protein, rat; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D015534:Trans-Activators; D020932:Nerve Growth Factor; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine