Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 42 (6), 441-447

Neurodevelopmental Aspects of RASopathies

Affiliations

Neurodevelopmental Aspects of RASopathies

Ye Eun Kim et al. Mol Cells.

Abstract

RAS gene mutations are frequently found in one third of human cancers. Affecting approximately 1 in 1,000 newborns, germline and somatic gain-of-function mutations in the components of RAS/mitogen-activated protein kinase (RAS/MAPK) pathway has been shown to cause developmental disorders, known as RASopathies. Since RAS-MAPK pathway plays essential roles in proliferation, differentiation and migration involving developmental processes, individuals with RASopathies show abnormalities in various organ systems including central nervous system. The frequently seen neurological defects are developmental delay, macrocephaly, seizures, neurocognitive deficits, and structural malformations. Some of the defects stemmed from dysregulation of molecular and cellular processes affecting early neurodevelopmental processes. In this review, we will discuss the implications of RAS-MAPK pathway components in neurodevelopmental processes and pathogenesis of RASopathies.

Keywords: RAS; RASopathy; neurodevelopment.

Conflict of interest statement

Disclosure

The authors have no potential conflicts of interest to disclose.

Figures

Fig. 1
Fig. 1. The role of RAS pathway in neurodevelopmental process
(A) The simplified view of the corticogenesis. For more detail information, refer to Hanashima and Toma (2015); Paridaen and Huttner (2014). The neurodevelopmental process progresses from left to right. Neuronal differentiation, proliferation of glial lineage cells, and oligodendrocyte differentiation and myelination occur at the same time in different cell types. (B) The role of components in the RAS/MAPK pathway in neurodevelopmental process. Each column is listed in the chronological order roughly, matching with Figure 1A. Red represents that the corresponding proteins promotes the step of column, in contrast, green means that the corresponding proteins suppresses the step of column. Gray indicates that the relationship of gene and each step is unknown. Yellow indicates that the genes are involved in each step, but it is uncertain that those genes promote or suppress the process. Of note, NF1 is a negative regulator of RAS/MAPK pathway, unlike the other genes. (C) The RAS/MAPK pathway and the disorders involving somatic/germline mutations of related genes. RTK, receptor tyrosine kinase; Nf1, neurofibromatosis type 1.

Similar articles

See all similar articles

Cited by 2 PubMed Central articles

References

    1. Aoki K. Local phosphatidylinositol 3,4,5-trisphosphate accumulation recruits Vav2 and Vav3 to activate Rac1/Cdc42 and initiate neurite outgrowth in nerve growth factor-stimulated PC12 cells. Mol Biol Cell. 2005;16:2207–2217. doi: 10.1091/mbc.e04-10-0904. - DOI - PMC - PubMed
    1. Aoki Y., Niihori T., Kawame H., Kurosawa K., Ohashi H., Tanaka Y., Filocamo M., Kato K., Suzuki Y., Kure S., et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet. 2005;37:1038–1040. doi: 10.1038/ng1641. - DOI - PubMed
    1. Arendt T., Gärtner U., Seeger G., Barmashenko G., Palm K., Mittmann T., Yan L., Hümmeke M., Behrbohm J., Brückner M.K., et al. Neuronal activation of Ras regulates synaptic connectivity. Eur J Neurosci. 2004;19:2953–2966. doi: 10.1111/j.0953-816X.2004.03409.x. - DOI - PubMed
    1. Bajenaru M.L., Donahoe J., Corral T., Reilly K.M., Brophy S., Pellicer A., Gutmann D.H. Neurofibromatosis 1 (NF1) heterozygosity results in a cell-autonomous growth advantage for astrocytes. Glia. 2001;33:314–323. doi: 10.1002/1098-1136(20010315)33:4<314::AID-GLIA1030>3.0.CO;2-Q. - DOI - PubMed
    1. Bajenaru M.L., Zhu Y., Hedrick N.M., Donahoe J., Parada L.F., Gutmann D.H. Astrocyte-specific inactivation of the neurofibromatosis 1 gene (NF1) is insufficient for astrocytoma formation. Mol Cell Biol. 2002;22:5100–5113. doi: 10.1128/MCB.22.14.5100-5113.2002. - DOI - PMC - PubMed
Feedback