Cripto-1 and Cripto-3 differential expression pattern in human placenta, umbilical cord and fetal tissues suggests new functions for these proteins

Cripto-1 (CR1) is an oncofetal protein involved in EGF/TGFβ signal transduction, with important functions in development, stem cell biology and cancer. Its homolog, Cripto-3 (CR3), is almost identical, with the exception of six (out of 188) amino acids. Thus, until recently, no antibody could distinguish them. Here, we compare the immunostaining pattern for highly specific monoclonal antibodies against CR1 and CR3 in human samples of placenta, umbilical cord and fetal tissues. Immunoreactivity (IR) for both proteins was found in placenta, umbilical cord, fetal retina, testis, lung, esophagus, pancreas and kidney, but was absent in samples of fetal heart, brain, liver and thymus. Nevertheless, a very different staining pattern emerged for CR1 and CR3 in the positive tissues. For instance, (i) CR1-IR in the placenta, umbilical cord and fetal esophagus was preferently found in cell nuclei whereas CR3-IR was always cytoplasmic; (ii) In endothelial cells, CR1 staining was always stronger than CR3´s; (iii) In the retina and the testes, CR3-IR was stronger than CR1´s in Müller cells and fetal spermatogonias; (iv) The epithelium of the fetal bronchioles was very faint for CR1 and strongly positive for CR3; and (v) Both CR1 and CR3 stained the fetal pancreatic islets, but CR1-IR was stronger than CR3´s in the peripheral cells of the islets. All these morphological differences in staining pattern point to complex nuances in Cripto biology that were not evident previously, including the nuclear localization of CR1, and these need to be addressed through molecular and physiological approaches.