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Updated: Jun 28, 2026
Isolation of Whole Cell Protein Lysates from Mouse Facial Processes and Cultured Palatal Mesenchyme Cells for Phosphoprotein Analysis
Published on: April 1, 2022
Mouse and human phenotypes indicate a critical conserved role for ERK2 signaling in neural crest development
Jason Newbern1, Jian Zhong, Rasika S Wickramasinghe
1Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Abstract:
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 approximately 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.
Insights
Haplo-insufficient ERK2 expression due to a 22q11.2 micro-deletion causes developmental defects in neural crest cells, leading to craniofacial and cardiac anomalies. This highlights ERK2
Area of Science:
- Developmental Biology
- Genetics
- Molecular Biology
Background:
- Disrupted ERK1/2 (MAPK3/MAPK1) signaling is linked to human developmental syndromes.
- Mutations in ERK1 or ERK2 have not been previously described.
- Neural crest cells are crucial for craniofacial and cardiac development.
Purpose of the Study:
- To investigate the role of ERK2 in neural crest development.
- To identify the genetic cause of developmental anomalies in patients with a 22q11.2 micro-deletion.
- To elucidate the signaling pathway involved in these defects.
Main Methods:
- Analysis of patients with a 1 Mb micro-deletion in distal 22q11.2.
- Conditional inactivation of ERK2 in mouse neural crest cells.
- Inactivation of upstream (B-Raf, C-Raf, MEK1, MEK2) and downstream (serum response factor) elements of the ERK cascade.
Main Results:
- Patients with the 22q11.2 micro-deletion exhibited haplo-insufficient ERK2 expression.
- These patients presented with conotruncal and craniofacial anomalies.
- Mouse models with conditional ERK2 inactivation showed similar developmental defects.
- Inactivation of other pathway components also led to analogous defects.
Conclusions:
- Mammalian neural crest development critically depends on the RAF/MEK/ERK/serum response factor signaling pathway.
- Deficiencies in neural crest autonomous ERK2 signaling explain the defects in patients with distal 22q11.2 micro-deletion.
- This study identifies ERK2 as a key player in neural crest development and associated human syndromes.
