title: LIM homeobox 8 (Lhx8) is a key regulator of the cholinergic neuronal function via a tropomyosin receptor kinase A (TrkA)-mediated positive feedback loop.
abstract: Basal forebrain cholinergic neurons play an important role in cognitive functions such as learning and memory, and they are affected in several neurodegenerative diseases, including Alzheimer disease and Down syndrome. Despite their functional importance, the molecular mechanisms of functional maturation and maintenance of these cholinergic neurons after the differentiation stage have not been fully elucidated. This study demonstrates that the LIM homeobox 8 (Lhx8) transcription factor regulates cholinergic function in rat septal cholinergic neurons in primary cultures from E18.5 embryos and in the adult brain. Lhx8 expression modulated tropomyosin receptor kinase A (TrkA) expression in septal cholinergic neurons in vitro and in vivo, resulting in regulated acetylcholine release as an index of cholinergic function. In addition, Lhx8 expression and function were regulated by nerve growth factor (NGF), and the effect of NGF was potentiated by Lhx8-induced TrkA expression. Together, our findings suggest that positive feedback regulation between Lhx8, TrkA, and NGF is an important regulatory mechanism for cholinergic functions of the septum.
authors.affiliation: From the Department of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582 and.
authors.forename: Takeyasu
authors.initials: T
authors.lastname: Tomioka
authors.forename: Takuya
authors.initials: T
authors.lastname: Shimazaki
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yamauchi
authors.forename: Toru
authors.initials: T
authors.lastname: Oki
authors.forename: Makoto
authors.initials: M
authors.lastname: Ohgoh
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D059329:Cholinergic Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D025461:Feedback, Physiological; D015870:Gene Expression / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D020932:Nerve Growth Factor / Q000378:metabolism / Q000494:pharmacology; D016716:PC12 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C112960:LIM homeobox protein 8; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D000109:Acetylcholine
keywords: Cell Signaling; Cholinergic Neuron; LIM Homeobox; Nerve Growth Factor; Neurons; Neurotrophic Factor; Receptor Tyrosine Kinase; Transcription Factors; TrkA