Cryptic, also known at CFC-1, was originally identified as a secreted protein that is specifically expressed during mesoderm differentiation (1). Cryptic, along with Cripto, Xenopus FRL-1 and zebrafish OEP (one-eyed pinhead) define the epidermal growth factor-CriptoFRL1Cryptic (EGF-CFC) family of signaling proteins that function in cancer and various developmental processes (2, 3). Overall sequence identity between members of the family is low, but they do share distinct domains: a variant EGF-like motif, a novel conserved cysteine-rich domain (called CFC domain), and a C-terminal hydrophobic region (2). Most EGF-CFC members have a glycosyl-phosphatidylinositol (GPI) anchoring site at the C-terminus and exist as extracellular membrane-anchored proteins. However, naturally-occurring soluble isoforms also exist. Human Cryptic shares 55% and 25% amino acid idenitity with mouse Cryptic and human Cripto, respectively. Despite weak conservation in amino acid identity, EGF-CFC family members appear to function similarly in assays for phenotypic rescue of zebrafish oep mutants (2).
Cryptic is expressed during gastrulation in the mesoderm and later in the neuroectoderm, marking the prospective floor plate of the neural tube (1). Genetic evidence from mice and humans points to a role for Cryptic in determining left-right asymmetry. Mutations in the cryptic gene result in a spectrum of heart, lung and spleen defects, all representing left-right laterality defects (4, 5). These phenotypes resemble some Nodal mutant alleles suggesting that Cryptic, like Cripto, acts as an essential co-factor for Nodal signaling (1, 3). Studies have shown that other TGF-beta superfamily members involved in mesoderm induction and left-right patterning, Vg1 and GDF-1, also require EGF-CFC co-factors. Cryptic binds to GDF-1 leading to an Act RIIB-ALK4-Cryptic-GDF-1 complex for signaling (6).
