The zinc finger transcription factor Klf7 is required for TrkA gene expression and development of nociceptive sensory neurons.
TrkA, the high affinity receptor for nerve growth factor (NGF), is essential for the development of nociceptive sensory and sympathetic neurons. The zinc finger transcription factor Klf7 interacts with an important cis element of the TrkA minimal enhancer and is coexpressed with TrkA in these neurons. We show that Klf7 binds to the endogenous TrkA minimal enhancer and can activate transcription from the TrkA minimal enhancer in a sequence-dependent manner. In Klf7(-/-) newborn mice, we find a significant reduction in sensory neurons due to increased apoptosis. The neuronal loss is restricted to nociceptive neurons that normally depend on TrkA for neurotrophic support, while other populations of somatosensory neurons appear normal. The reduction of TrkA expression in sensory neurons is a direct effect of Klf7 gene ablation, rather than a secondary effect of cell death. As a result, Klf7(-/-) mice have deficient response to noxious stimuli. Finally, removal of one TrkA allele exacerbates the loss of TrkA(+) neurons in Klf7(-/-) mice. Thus, Klf7 specifically regulates TrkA gene expression and is required for the development of a subset of nociceptive sensory neurons.
Lei
Lei
L
Center for Developmental Biology and Kent Waldrep Center for Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, 75390-9133, USA.
Laub
Friedrich
F
Lush
Mark
M
Romero
Mario
M
Zhou
Jing
J
Luikart
Bryan
B
Klesse
Laura
L
Ramirez
Francesco
F
Parada
Luis F
LF
D000483:Alleles; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D049109:Cell Proliferation; D002478:Cells, Cultured; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000502:physiology*; D004742:Enhancer Elements, Genetic; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D020287:In Situ Nick-End Labeling; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D020932:Nerve Growth Factor / Q000494:pharmacology; D009475:Neurons, Afferent / Q000166:cytology* / Q000187:drug effects; D011247:Pregnancy; D020917:Receptor, trkA / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000502:physiology*
D017931:DNA Primers; D004268:DNA-Binding Proteins; C426008:Klf7 protein, mouse; D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors; D020932:Nerve Growth Factor; D020917:Receptor, trkA