title: Interaction of Brn3a and HIPK2 mediates transcriptional repression of sensory neuron survival.
abstract: 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.
authors.affiliation: Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Wiggins
authors.forename: Guangwei
authors.initials: G
authors.lastname: Wei
authors.forename: Epaminondas
authors.initials: E
authors.lastname: Doxakis
authors.forename: Connie
authors.initials: C
authors.lastname: Wong
authors.forename: Amy A
authors.initials: AA
authors.lastname: Tang
authors.forename: Keling
authors.initials: K
authors.lastname: Zang
authors.forename: Esther J
authors.initials: EJ
authors.lastname: Luo
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.forename: Louis F
authors.initials: LF
authors.lastname: Reichardt
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Huang
mesh_terms: 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
chemical_list: 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