Modeling RASopathies with Genetically Modified Mouse Models

Abstract

The RAS/MAPK signaling pathway plays key roles in development, cell survival and proliferation, as well as in cancer pathogenesis. Molecular genetic studies have identified a group of developmental syndromes, the RASopathies, caused by germ line mutations in this pathway. The syndromes included within this classification are neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NS-ML, formerly known as LEOPARD syndrome), Costello syndrome (CS), cardio-facio-cutaneous syndrome (CFC), Legius syndrome (LS, NF1-like syndrome), capillary malformation-arteriovenous malformation syndrome (CM-AVM), and hereditary gingival fibromatosis (HGF) type 1. Although these syndromes present specific molecular alterations, they are characterized by a large spectrum of functional and morphological abnormalities, which include heart defects, short stature, neurocognitive impairment, craniofacial malformations, and, in some cases, cancer predisposition. The development of genetically modified animals, such as mice (Mus musculus), flies (Drosophila melanogaster), and zebrafish (Danio rerio), has been instrumental in elucidating the molecular and cellular bases of these syndromes. Moreover, these models can also be used to determine tumor predisposition, the impact of different genetic backgrounds on the variable phenotypes found among the patients and to evaluate preventative and therapeutic strategies. Here, we review a wide range of genetically modified mouse models used in the study of RASopathies and the potential application of novel technologies, which hopefully will help us resolve open questions in the field.

Characterization of a new B-ALL cell line with constitutional defect of the Notch signaling pathway

“…Some rare and inherited diseases are characterized by molecular lesions promoting cancer diseases [ 23 ]. For example, RASopathies, such as Noonan syndrome, Neurofibromatosis 1 and Leopard syndrome, are a subtype of developmental diseases characterized by mutations in genes encoding for components of the Ras/MAPK pathway ( NF1 , PTPN1 , SOS1, RAF1, KRAS, NRAS, SHOC2, CBL ) [ 24 , 25 ]. RASopathies are associated to higher risk to develop AML, ALL and Myeloproliferative/Myelodysplastic syndromes [ 26 – 28 ].…”

Clinical and molecular characterization of children with Noonan syndrome and other RASopathies in Argentina

“…[5][6][7][8][9] Approximately 70-80 % of patients with NS have these gene mutations. 10 The causative mutations have not been identified in the other 20-30 %. 11 De novo mutations account for 60 % of NS cases.…”

Craniofacial, orofacial and dental disorders: the role of the RAS/ERK pathway

“…However, the features they display often depend on the genetic background of the animals and attention should be paid during experimentation and phenotypic evaluation (Ref. 9). Increased levels of phosphorylated Erk1/2 are detected in the frontal bones of Wnt1-Cre;Shp2 Q79R mice displaying growth retardation and craniofacial abnormalities (Ref.…”

“…Mutations in the components of this particular pathway can lead to some of the most common skull and face disorders in humans. In addition to RASopathies that are well studied and reviewed elsewhere (Refs 8, 9), a variety of craniosynostosis cases as well as orofacial abnormalities, such as cleft lip and palate, spring from dysregulation of the RAS/ERK pathway activation. This review focuses on all these cases and is divided into three main sections representing the corresponding areas of research: (1) orofacial development with respect to palate and mandibular formation, (2) craniofacial development with respect to calvarial bone and suture formation and (3) dental development including studies of enamel, dentine and cementum generation.…”