Disruption of the ERK/MAPK pathway in neural crest cells as a potential cause of Pierre Robin sequence

Abstract

Disrupted ERK1/2 signaling is associated with several developmental syndromes in humans. To understand the function of ERK2 (MAPK1) in the postmigratory neural crest populating the craniofacial region, we studied two mouse models: Wnt1-Cre;Erk2 fl/fl and Osr2-Cre;Erk2 fl/fl . Wnt1-Cre;Erk2 fl/fl mice exhibited cleft palate, malformed tongue, micrognathia and mandibular asymmetry. Cleft palate in these mice was associated with delay/failure of palatal shelf elevation caused by tongue malposition and micrognathia. Osr2-Cre;Erk2 fl/fl mice, in which the Erk2 deletion is restricted to the palatal mesenchyme, did not display cleft palate, suggesting that palatal clefting in Wnt1-Cre; Erk2 fl/fl mice is a secondary defect. Tongues in Wnt1-Cre;Erk2 fl/fl mice exhibited microglossia, malposition, disruption of the muscle patterning and compromised tendon development. The tongue phenotype was extensively rescued after culture in isolation, indicating that it might also be a secondary defect. The primary malformations in Wnt1-Cre;Erk2 fl/fl mice, namely micrognathia and mandibular asymmetry, are linked to an early osteogenic differentiation defect. Collectively, our study demonstrates that mutation of Erk2 in neural crest derivatives phenocopies the human Pierre Robin sequence and highlights the interconnection of palate, tongue and mandible development. Because the ERK pathway serves as a crucial point of convergence for multiple signaling pathways, our study will facilitate a better understanding of the molecular regulatory mechanisms of craniofacial development.

Ablation of the Sox11 Gene Results in Clefting of the Secondary Palate Resembling the Pierre Robin Sequence

“…We thus provide evidence that extrinsic influence is the major factor in clefting of the secondary palate of the Sox11 mutant, resembling the human PRS. Similar murine models have been revealed in the Prdm16 loss-of-function mutant and loss of mesenchymal signaling for Erk2 or Fgfr (12,14,40).…”

MEMO1 drives cranial endochondral ossification and palatogenesis

“…Future studies will need to address the full extent of MEMO1’s role during palatogenesis and suckling as well as how structures such as the cranial base and tongue – potentially via defects in hyoid ossification - may be influencing these events. Note that defects in the cranial base would provide an additional mechanism by which closure of the palate could be linked with abnormalities in an extrinsic developmental process, alongside a failure of descent of the tongue, as has previously been described 76 . Teasing out these developmental relationships will be critical as cranial base defects have been associated with a variety of craniofacial anomalies, including isolated cleft palate.…”

A Review of Orofacial Clefting and Current Genetic Mouse Models

“…can modulate this same protein kinase cascade, and each of the molecules listed is also known to be involved with development of the palate [17]. Additionally, analysis of the potential spatial representation of active (phosphorylated) ERK1/ERK2 in the palate has resulted in the discovery this pathway persists in both the epithelium and the mesenchyme associated with the developing palatal shelves [17].…”

“…Additionally, analysis of the potential spatial representation of active (phosphorylated) ERK1/ERK2 in the palate has resulted in the discovery this pathway persists in both the epithelium and the mesenchyme associated with the developing palatal shelves [17].…”

“…Research has also shown associations between MAPK signaling and growth factor pathway genes that include Fgf9/10/18, Alk5, and Itgb1 among others and vary craniofacial clefting and defects in mice, including mandibular osteogenic and tongue abnormalities [17]. The inclusion of the mandible and tongue is important in that it adds to the overall complexity of the defect, thus making treatment options that much more of a priority.…”