Direct autoregulation and gene dosage compensation by POU-domain transcription factor Brn3a.
Brn3a is a POU-domain transcription factor expressed in peripheral sensory neurons and in specific interneurons of the caudal CNS. Sensory expression of Brn3a is regulated by a specific upstream enhancer, the activity of which is greatly increased in Brn3a knockout mice, implying that Brn3a negatively regulates its own expression. Brn3a binds to highly conserved sites within this enhancer, and alteration of these sites abolishes Brn3a regulation of reporter transgenes. Furthermore, endogenous Brn3a expression levels in the sensory ganglia of Brn3a(+/+) and Brn3a(+/-) mice are similar, demonstrating that autoregulation can compensate for the loss of one allele by increasing transcription of the remaining gene copy. Conversely, transgenic overexpression of Brn3a in the trigeminal ganglion suppresses the expression of the endogenous gene. These findings demonstrate that the Brn3a locus functions as a self-regulating unit to maintain a constant expression level of this key regulator of neural development.
Trieu
May
M
Department of Psychiatry, University of California, San Diego and San Diego VA Medical Center, La Jolla, CA 92093-0603, USA.
Ma
Ann
A
Eng
S Raisa
SR
Fedtsova
Natalia
N
Turner
Eric E
EE
D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D002490:Central Nervous System / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D003001:Cloning, Molecular; D017124:Conserved Sequence; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D017950:Ganglia, Sensory / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental; D006706:Homeostasis; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009475:Neurons, Afferent / Q000502:physiology; D017434:Protein Structure, Tertiary; D050818:Transcription Factor Brn-3; D050819:Transcription Factor Brn-3A; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
D004268:DNA-Binding Proteins; C494188:POU4F1 protein, human; C494189:Pou4f1 protein, mouse; D050818:Transcription Factor Brn-3; D050819:Transcription Factor Brn-3A; D014157:Transcription Factors