Mouse and human phenotypes indicate a critical conserved role for ERK2 signaling in neural crest development

Jason Newbern, Jian Zhong, S. Rasika Wickramasinghe, Xiaoyan Li, Yaohong Wu, Ivy Samuels, Natalie Cherosky, J. Colleen Karlo, Brianne O'Loughlin, Jamie Wikenheiser, Madhusudhana Gargesha, Yong Qiu Doughman, Jean Charron, David D. Ginty, Michiko Watanabe, Sulagna C. Saitta, William D. Snider, Gary E. Landreth

Research output: Contribution to journalArticlepeer-review

140 Scopus citations


Disrupted ERK1/2 (MAPK3/MAPK1) MAPK signaling has been associated with several developmental syndromes in humans; however, mutations in ERK1 or ERK2 have not been described. We demonstrate haplo-insufficient ERK2 expression in patients with a novel ≈1 Mb micro-deletion in distal 22q11.2, a region that includes ERK2. These patients exhibit conotruncal and craniofacial anomalies that arise from perturbation of neural crest development and exhibit defects comparable to the DiGeorge syndrome spectrum. Remarkably, these defects are replicated in mice by conditional inactivation of ERK2 in the developing neural crest. Inactivation of upstream elements of the ERK cascade (B-Raf and C-Raf, MEK1 and MEK2) or a downstream effector, the transcription factor serum response factor resulted in analogous developmental defects. Our findings demonstrate that mammalian neural crest development is critically dependent on a RAF/MEK/ERK/serum response factor signaling pathway and suggest that the craniofacial and cardiac outflow tract defects observed in patients with a distal 22q11.2 micro-deletion are explained by deficiencies in neural crest autonomous ERK2 signaling.

Original languageEnglish (US)
Pages (from-to)17115-17120
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number44
StatePublished - Nov 4 2008
Externally publishedYes


  • 22q11 microdeletion
  • Human syndromes
  • MAP kinase

ASJC Scopus subject areas

  • General


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