Introduction:
Cells receive molecular cues from the extracellular matrix through receptors located at the cell membrane to regulate pivotal functions such as cell proliferation, migration, and differentiation. The signals from outside of cells are transmitted through adaptor proteins and guanine nucleotide exchange factors to small GTPases, which activate the downstream targets subsequently. Maintenance of these signaling pathways is of critical importance in cell survival and organism development. On the contrary, their perturbation can cause aberrant cell properties and abnormal tissue development. RAPGEF1 is a guanine nucleotide exchange factor transmitting signals from the extracellular matrix to the Ras family of GTPase, by modulating the Ras/Rap/MAPK pathway and Ras/Jun kinase pathway (Voss, Gruss, & Thomas, 2003; Voss, Krebs, & Thomas, 2006). RAPGEF1 was found to be present in a complex with CRK or GRB2/ASH, transducing signals from tyrosine kinases to RAS in a number of different tissues (Tanaka et al., 1994). The RAS-CRK-RAP1 cellular signal transduction system is regulated by guanine nucleotide exchange factors (GEFs), derangement of which could lead to carcinogenesis (Hirata et al., 2004).
Rapgef1 is essential for embryonic development, and Rapgef1 null mouse embryos died early in gestation (Ohba et al., 2001). Mice embryos with hypomorphic alleles of Rapgef1 could sustain longer, but still died due to blood vessel maturation defects (Voss et al., 2003). Rapgef1 is required for the formation of focal adhesion and vascular maturation, accounting for blood vessel development defect in mouse models (Voss et al., 2003). Rapgef1 has also been shown to regulate pathological angiogenesis in tumors by mediating platelet secretion (Martin-Granado et al., 2017). Further evidence exists for a role of Rapgef1 in myogenic differentiation through coordination cell cycle exit, actin dynamics and survival signaling (Sasi Kumar et al., 2015) and in the regulation of the cortical neural precursor population size through Rapgef1-mediated inhibition of the Ras signaling pathway (Voss et al., 2006). Mice lacking Rapgef1 had an increase in nuclear beta-catenin and a prominent increase of neural precursor proliferation in the cerebral cortex (Voss et al., 2006). Rapgef1-deficient mouse embryos also showed a failure of cortical neurons to migrate (Voss et al., 2008). Rapgef1 was shown to be involved in the multi-to-bipolar transition in mouse cortex during neuronal development, defects of which caused failure in neuronal migration, axon formation and cortical lamination (Shah et al., 2016).
There is no report of human Mendelian disease attributable toRAPGEF1 . We noted that, a relevant gene, namely, RAPGEF2(OMIM#609530), was supposed to be related to familial myoclonic epilepsy. Given the phenotype observed in the aforementionedRapgef1 mouse models, it is reasonable to hypothesize that the hypomorphic alleles of RAPGEF1 may cause problems in multiple systems especially brain and vessel. Zebrafish is a widely used organismal model for mimicry of human developmental disorders. Recapitulating human phenotype by zebrafish models can provide insights into the molecular mechanism of RAPGEF1 defects.