Abnormal sympathetic nervous system development and physiological dysautonomia in Egr3-deficient mice.
Sympathetic nervous system development depends upon many factors that mediate neuron migration, differentiation and survival. Target tissue-derived nerve growth factor (NGF) signaling-induced gene expression is required for survival, differentiation and target tissue innervation of post-migratory sympathetic neurons. However, the transcriptional regulatory mechanisms mediated by NGF signaling are very poorly defined. Here, we identify Egr3, a member of the early growth response (Egr) family of transcriptional regulators, as having an important role in sympathetic nervous system development. Egr3 is regulated by NGF signaling and it is expressed in sympathetic neurons during development when they depend upon NGF for survival and target tissue innervation. Egr3-deficient mice have severe sympathetic target tissue innervation abnormalities and profound physiological dysautonomia. Unlike NGF, which is essential for sympathetic neuron survival and for axon branching within target tissues, Egr3 is required for normal terminal axon extension and branching, but not for neuron survival. The results indicate that Egr3 is a novel NGF signaling effector that regulates sympathetic neuron gene expression required for normal target tissue innervation and function. Egr3-deficient mice have a phenotype that is remarkably similar to humans with sympathetic nervous system disease, raising the possibility that it may have a role in some forms of human dysautonomia, most of which have no known cause.
Eldredge
Laurie C
LC
Department of Pathology, Northwestern University, Chicago, IL 60611, USA.
Gao
Xiaoguang M
XM
Quach
David H
DH
Li
Lin
L
Han
Xiaoqiang
X
Lomasney
Jon
J
Tourtellotte
Warren G
WG
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D047068:Arylalkylamine N-Acetyltransferase / Q000378:metabolism; D001342:Autonomic Nervous System Diseases / Q000151:congenital*; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D001763:Blepharoptosis / Q000473:pathology / Q000503:physiopathology; D002465:Cell Movement / Q000187:drug effects; D051776:Early Growth Response Protein 3 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006321:Heart / Q000294:innervation; D051379:Mice; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010870:Pineal Gland / Q000187:drug effects / Q000201:enzymology / Q000294:innervation; D015398:Signal Transduction / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000166:cytology / Q000187:drug effects / Q000196:embryology* / Q000503:physiopathology*
C497369:Egr3 protein, mouse; D051776:Early Growth Response Protein 3; D020932:Nerve Growth Factor; D047068:Arylalkylamine N-Acetyltransferase