The scaffold protein Shoc2 controls ERK1/2‐driven neural crest development by balancing the expression of extracellular matrix components

Abstract

Dysregulation of the extracellular‐signal‐regulated kinase 1/2 (ERK1/2) pathway results in common developmental syndromes – RASopathies. Our lab studies a RASopathy called Noonan syndrome with loose anagen hair (NSLAH). This RASopathy is caused by mutations in a critical regulator of the ERK1/2 pathway, Shoc2. Patients harboring shoc2mutations have structural deficiencies common among RASopathies (e.g., altered pigmentation, craniofacial defects, valve disorders). Many NSLAH features could involve defects in the development of neural crest (NC).Zebrafish provide an excellent system for studying neural crest development because of their transparency and highly conserved molecular pathways. Therefore, we utilized the zebrafish model to study the role of Shoc2‐mediated signals in NC development. We found that the loss of Shoc2 affects the expression of the transcription factors prdm1a, pax7, and foxd3‐ all required for the neural plate border formation in zebrafish. The loss of Shoc2 also led to the irregular expression of sox10, the global regulator of NC formation. Moreover, embryos depleted of Shoc2 displayed altered expression of dlx2a, a key transcription factor for the maintenance of cranial NCCs and their migration. We observed that loss of Shoc2 impaired the expression of the transcription factor inducing commitment to cartilage fate, promoting the activation of cartilage‐specific genes in the forebrain and the pharyngeal arch regions, and regulating chondrocyte stacking, sox9a. Moreover, the loss of the Shoc2‐ERK1/2 axis hindered the terminal differentiation of NCCs and resulted in the reduced number of NCC‐derived Schwann cells and pigment cells, including iridophores. Finally, our global assessment of the transcription programs affected by the loss of the Shoc2‐ERK1/2 signals revealed striking differences in the expression of a significant number of extracellular matrix proteins and proteoglycans, including collagen2aI, and aggrecans a and b ‐ all of which are critical for chondrocyte differentiation and maturation.Together, our data suggest that the Shoc2‐ERK1/2 signaling axis is critical for the development, specification/differentiation, and morphogenesis of the NC‐derived tissues. Our study is the first to define that Shoc2‐mediated ERK1/2 signals regulate NC development. Future inquiries into the mechanisms by which Shoc2 controls embryogenesis will significantly advance our understanding of the mechanisms underlying pathological causes of NSLAH and, ultimately, other RASopathies.