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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Apoptosis
-
Blotting, Western
-
Carrier Proteins / physiology*
-
Cell Survival
-
DNA / metabolism
-
DNA, Complementary / metabolism
-
DNA-Binding Proteins / physiology*
-
Down-Regulation
-
Exons
-
Gene Deletion
-
Gene Expression Regulation*
-
Gene Targeting
-
Green Fluorescent Proteins / metabolism
-
Immunohistochemistry
-
Immunoprecipitation
-
In Situ Hybridization
-
Luciferases / metabolism
-
Mice
-
Models, Biological
-
Models, Genetic
-
Mutation
-
Neurons / metabolism
-
Protein Binding
-
Protein Serine-Threonine Kinases / physiology*
-
Protein Structure, Tertiary
-
Proto-Oncogene Proteins c-bcl-2 / metabolism
-
RNA, Messenger / metabolism
-
Receptor, trkA / metabolism
-
Reverse Transcriptase Polymerase Chain Reaction
-
Time Factors
-
Transcription Factor Brn-3
-
Transcription Factor Brn-3A
-
Transcription Factors / physiology*
-
Transcription, Genetic
-
Two-Hybrid System Techniques
-
Up-Regulation
-
bcl-X Protein
Substances
-
Bcl2l1 protein, mouse
-
Carrier Proteins
-
DNA, Complementary
-
DNA-Binding Proteins
-
Pou4f1 protein, mouse
-
Proto-Oncogene Proteins c-bcl-2
-
RNA, Messenger
-
Transcription Factor Brn-3
-
Transcription Factor Brn-3A
-
Transcription Factors
-
bcl-X Protein
-
Green Fluorescent Proteins
-
DNA
-
Luciferases
-
Hipk2 protein, mouse
-
Receptor, trkA
-
Protein Serine-Threonine Kinases