Ras/MAPK dysregulation in development causes a skeletal myopathy in an activating BrafL597V mouse model for cardio-facio-cutaneous syndrome.
Dev Dyn
; 250(8): 1074-1095, 2021 08.
Article
en En
| MEDLINE
| ID: mdl-33522658
ABSTRACT
BACKGROUND:
Cardio-facio-cutaneous (CFC) syndrome is a human multiple congenital anomaly syndrome that is caused by activating heterozygous mutations in either BRAF, MEK1, or MEK2, three protein kinases of the Ras/mitogen-activated protein kinase (MAPK) pathway. CFC belongs to a group of syndromes known as RASopathies. Skeletal muscle hypotonia is a ubiquitous phenotype of RASopathies, especially in CFC syndrome. To better understand the underlying mechanisms for the skeletal myopathy in CFC, a mouse model with an activating BrafL597V allele was utilized.RESULTS:
The activating BrafL597V allele resulted in phenotypic alterations in skeletal muscle characterized by a reduction in fiber size which leads to a reduction in muscle size which are functionally weaker. MAPK pathway activation caused inhibition of myofiber differentiation during embryonic myogenesis and global transcriptional dysregulation of developmental pathways. Inhibition in differentiation can be rescued by MEK inhibition.CONCLUSIONS:
A skeletal myopathy was identified in the CFC BrafL597V mouse validating the use of models to study the effect of Ras/MAPK dysregulation on skeletal myogenesis. RASopathies present a novel opportunity to identify new paradigms of myogenesis and further our understanding of Ras in development. Rescue of the phenotype by inhibitors may help advance the development of therapeutic options for RASopathy patients.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Displasia Ectodérmica
/
Músculo Esquelético
/
Proteínas Quinasas Activadas por Mitógenos
/
Proteínas Proto-Oncogénicas B-raf
/
Insuficiencia de Crecimiento
/
Cardiopatías Congénitas
/
Enfermedades Musculares
Tipo de estudio:
Etiology_studies
Límite:
Animals
Idioma:
En
Revista:
Dev Dyn
Asunto de la revista:
ANATOMIA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos