BMP9 (bone morphogenetic protein 9) induces NGF as an autocrine/paracrine cholinergic trophic factor in developing basal forebrain neurons.
Acetylcholine (ACh) synthesis and release from basal forebrain cholinergic neurons (BFCN) innervating the cerebral cortex and hippocampus are essential processes for normal learning, memory and attention. Bone morphogenetic protein (BMP) 9 is a cholinergic differentiation factor in the developing septum that increases ACh synthesis and choline acetyltransferase (Chat) gene expression both in vivo and in vitro. We investigated the possible induction of cholinergic trophic factors by BMP9 in murine septal cells. Nerve growth factor (NGF) protein expression and secretion into the medium was increased in cultured embryonic septal cells treated with BMP9, and partially mediated BMP9-induced acetylcholine production and Chat gene expression. BMP9-induced Ngf gene expression was detected in postmitotic cells, required new protein synthesis and was blocked by BMP type I receptor inhibition. Cholinergic neurons were isolated by fluorescence-activated cell sorting based on either transgenic expression of green fluorescent protein driven by the Chat promoter or NGF receptor (p75) immunostaining. Although both noncholinergic and cholinergic neurons in untreated cultures expressed similar low levels of Ngf, increased Ngf gene expression was restricted to Chat-positive neurons in BMP9-treated cultures. Likewise, similar levels of Ngf mRNA were detected in p75-negative and p75-positive septal cells, yet only p75-positive BFCN increased their Ngf gene expression when treated with BMP9, and only these cells expressed the Alk1 BMP receptor. The data suggest an autocrine/paracrine role for NGF in the development and/or maintenance of BFCN and imply that the stimulation of NGF production and release contributes to the cholinergic-supportive properties of BMP9.
Schnitzler
Aletta C
AC
Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Mellott
Tiffany J
TJ
Lopez-Coviella
Ignacio
I
Tallini
Yvonne N
YN
Kotlikoff
Michael I
MI
Follettie
Maximillian T
MT
Blusztajn
Jan Krzysztof
JK
D000109:Acetylcholine / Q000378:metabolism*; D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D002795:Choline O-Acetyltransferase / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D055427:Growth Differentiation Factor 2 / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects*; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D020665:Septum of Brain / Q000166:cytology* / Q000196:embryology*
C526108:Gdf2 protein, mouse; D055427:Growth Differentiation Factor 2; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D020800:Receptor, Nerve Growth Factor; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D002795:Choline O-Acetyltransferase; D000109:Acetylcholine