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.