Interaction of Brn3a and HIPK2 mediates transcriptional repression of sensory neuron survival.
The Pit1-Oct1-Unc86 domain (POU domain) transcription factor Brn3a controls sensory neuron survival by regulating the expression of Trk receptors and members of the Bcl-2 family. Loss of Brn3a leads to a dramatic increase in apoptosis and severe loss of neurons in sensory ganglia. Although recent evidence suggests that Brn3a-mediated transcription can be modified by additional cofactors, the exact mechanisms are not known. Here, we report that homeodomain interacting protein kinase 2 (HIPK2) is a pro-apoptotic transcriptional cofactor that suppresses Brn3a-mediated gene expression. HIPK2 interacts with Brn3a, promotes Brn3a binding to DNA, but suppresses Brn3a-dependent transcription of brn3a, trkA, and bcl-xL. Overexpression of HIPK2 induces apoptosis in cultured sensory neurons. Conversely, targeted deletion of HIPK2 leads to increased expression of Brn3a, TrkA, and Bcl-xL, reduced apoptosis and increases in neuron numbers in the trigeminal ganglion. Together, these data indicate that HIPK2, through regulation of Brn3a-dependent gene expression, is a critical component in the transcriptional machinery that controls sensory neuron survival.
Wiggins
Amanda K
AK
Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA.
Wei
Guangwei
G
Doxakis
Epaminondas
E
Wong
Connie
C
Tang
Amy A
AA
Zang
Keling
K
Luo
Esther J
EJ
Neve
Rachael L
RL
Reichardt
Louis F
LF
Huang
Eric J
EJ
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002352:Carrier Proteins / Q000502:physiology*; D002470:Cell Survival; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D015536:Down-Regulation; D005091:Exons; D017353:Gene Deletion; D005786:Gene Expression Regulation; D018390:Gene Targeting; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D050818:Transcription Factor Brn-3; D050819:Transcription Factor Brn-3A; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D020798:Two-Hybrid System Techniques; D015854:Up-Regulation; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D002352:Carrier Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C494189:Pou4f1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D050818:Transcription Factor Brn-3; D050819:Transcription Factor Brn-3A; D014157:Transcription Factors; D051020:bcl-X Protein; D049452:Green Fluorescent Proteins; D004247:DNA; D008156:Luciferases; C492003:Hipk2 protein, mouse; D020917:Receptor, trkA; D017346:Protein Serine-Threonine Kinases