Teratocarcinoma-Derived Growth Factor 1

Cloning and Expression

From a teratocarcinoma cell line, Ciccodicola et al. (1989) isolated a human cDNA (referred to as CRIPTO by them) encoding a protein of 188 amino acids. The central portion of this protein shared structural similarities with the human transforming growth factor alpha (190170) and epidermal growth factor (EGF; 131530). Northern blot analysis of a wide variety of tumor and normal cell lines and tissues showed that CRIPTO transcripts are detected only in undifferentiated cells and disappear after cell differentiation induced by retinoic acid treatment.

Mapping

By Southern analysis of hamster/human somatic cell hybrids, Dono et al. (1991) mapped the CRIPTO gene to chromosome 3. Saccone et al. (1995) mapped the TDGF1 gene to 3p23-p21. Liguori et al. (1997) mapped the mouse Tdgf1 gene to murine chromosome 9 and 2 pseudogenes to chromosomes 16 and 17.

Gene Structure

Dono et al. (1991) determined that the CRIPTO gene is organized into 6 exons.

Liguori et al. (1996) described the isolation and characterization of the mouse Tdgf1 gene. Comparison of the human and mouse genes revealed a perfect conservation of the exon/intron structure of the region containing the EGF-like motif. In contrast, mouse exons 1 and 3 are shorter than the corresponding human exons. This difference results in a different N-terminus in the human and mouse proteins. Liguori et al. (1996) found that the mouse 'cripto' protein contains a canonical signal peptide that is absent in the human protein.

PSEUDOGENES

Dono et al. (1991) described the isolation and characterization of 2 human genomic CRIPTO-encoding sequences. One of these mapped to chromosome 3; the other, possibly a functional retroposon, mapped to the Xq21-q22 region. The mapping was done by Southern analysis of hamster/human somatic cell hybrids. They referred to these genomic clones as CR-1 (corresponding to the CRIPTO gene) and CR-3. The CR-3 sequence has all the characteristics of a retroposon, including a poly(A) tail and the lack of introns. Saccone et al. (1995) referred to the gene on Xq, which they considered a possible functional pseudogene, as TDGF3. The TDGF3 pseudogene had also been referred to as TDGF2.

In the mouse, Liguori et al. (1996) isolated and characterized 2 intronless sequences, designated Tdgf2 and Tdgf3 by them.

Gene Family

Shen and Schier (2000) reviewed the EGF-CFC (Cripto, Frl1, and Cryptic) gene family in vertebrate development. They noted that in mice, Cripto is required for germ-layer formation and the correct positioning of the anterior-posterior axis, whereas Cryptic (CFC1; 605194) is necessary for the determination of the left-right axis. Prior to gastrulation, Cripto expression is initially symmetric and uniform in the epiblast, and then becomes asymmetric in a proximal-distal gradient. Targeted disruption of the Cripto gene is lethal. Cripto and Cryptic are essential cofactors for Nodal (601265) family proteins, which are essential signaling molecules for mesoderm development.

Molecular Genetics

Cryptic protein is required for proper laterality development in humans. TDGF1, like CFC1, is an EGF-CFC family member and an obligate coreceptor involved in NODAL signaling, a developmental program implicated in midline, forebrain, and left-right axis development in model organisms. A mutation in the conserved CFC domain of the TDGF1 gene (187395.0001) was demonstrated by de la Cruz et al. (2002) in a patient with midline anomalies of the forebrain. The mutant protein was inactive in a zebrafish rescue assay, indicating a role for TDGF1 in human midline and forebrain development.