Identification of a Smad4/YY1-recognized and BMP2-responsive transcriptional regulatory module in the promoter of mouse GABA transporter subtype I (Gat1) gene.
GABAergic dysfunction is implicated in a variety of neurodevelopmental and psychiatric disorders. The mechanisms underlying GABAergic differentiation, however, are not well understood. GABA transporter 1 (Gat1; Slc6a1) is an essential component of the GABAergic system, and its ectopic mRNA expression may be responsible for GABAergic malfunction under different pathological conditions. Thus, monitoring the transcriptional regulation of gat1 may help to elucidate the mechanisms that govern the differentiation of GABAergic neurons. In this study, we identified a promoter region that is sufficient to recapitulate endogenous gat1 expression in transgenic mice. A 46 bp cis-regulator in the promoter sequence was responsible for the stimulation of bone morphogenetic protein-2 (BMP2) on gat1 expression in cortical cortex. Furthermore, our study demonstrated that Smad4 and YY1 are physically bound to the element and mediate both the negative and positive regulatory effects in which BMP2 can affect the balance. In summary, we have identified a Smad4/YY1-based bidirectional regulation model for GABAergic gene transcription and demonstrated a molecular cue important for the differentiation of GABAergic neurons.
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032, China.
Minghui
M
Yao
Gang
G
Niu
Zhejin
Z
Sheng
Zhugang
Z
Wang
Jian
J
Fei
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000502:physiology; D015536:Down-Regulation / Q000235:genetics; D050485:GABA Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic / Q000502:physiology*; D011485:Protein Binding / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics* / Q000502:physiology; D051901:Smad4 Protein / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics; D050986:YY1 Transcription Factor / Q000235:genetics* / Q000378:metabolism / Q000502:physiology
D055396:Bone Morphogenetic Protein 2; D050485:GABA Plasma Membrane Transport Proteins; D051901:Smad4 Protein; D050986:YY1 Transcription Factor