Homeoprotein hhex-induced conversion of intestinal to ventral pancreatic precursors results in the formation of giant pancreata in Xenopus embryos.

Mechanistic understanding of pancreas development and the formation of pancreatic β cell lineage is critical for developing rational strategies to generate functional pancreatic beta cells from human embryonic stem cells or induced pluripotent stem cells, which holds great potential for cell transplantation therapy of type I diabetes mellitus.

Using the frog, Xenopus laevis, as a model system, Dr. CHEN Yonglong’s lab at Guangzhou Institutes of Biomedicine and Health and Dr.ZHAO Hui’s lab at the Chinese University of Hong Kong discovered the active role of homeoprotein hhex in regulating the formation of ventral pancreatic precursor cells as early as gastrulation.

They identified a novel marker gene in frog embryos and named it as ventral pancreatic precursor 1 (vpp1).  vpp1 is differentially expressed in a cell population within the dorsal endoderm in a pattern partially overlapping with that of hhex during Xenopus gastrulation. In tail bud embryos, vpp1 expression specifically demarcates two ventral pancreatic buds, while hhex expression is mainly restricted to the liver diverticulum. Ectopic expression of a critical dose of hhex led to a greatly enlarged vpp1-positive domain and subsequently to the formation of giant ventral pancreata, putatively by conversion of intestinal to ventral pancreatic precursor cells. Conversely, antisense morpholino oligonucleotide-mediated knockdown of hhex resulted in a down-regulation of vpp1 expression and a specific loss of the ventral pancreas. Furthermore, titration of hhex with a dexamethasone-inducible hhex-VP16GR fusion construct suggested that endogenous hhex activity during gastrulation is essential for the formation of ventral pancreatic progenitor cells. These observations suggest that, beyond its role in liver development, hhex controls specification of a vpp1 positive endodermal cell population during gastrulation that is required for the formation of the ventral pancreas.

So far, it remains unclear how overexpression of hhex results in the robust level of ectopic vpp1 expression described here. Vegetal injection of hhex mRNA into the two ventral blastomeres of 4-cell stage embryos had no effect on liver or ventral pancreas development. Similarly, they found that overexpression of hhex in endodermalized animal cap cells was not sufficient to activate vpp1 and pancreatic marker expression. Together, these data suggest that unidentified co-factor(s) exist(s) in the dorsal endodermal cells, which cooperate(s) with hhex in converting these cells to vpp1-expressing cells.

This research has recently been published in Proceedings of the National Academy of Sciences of the United States of America (2012, 109:8594-8599), with ZHAO Hui and HAN Dandan as the co-first authors (http://www.ncbi.nlm.nih.gov/pubmed/22592794).

The work was funded by the National Basic Research Program of China (2009CB941202), the Deutsche Forschungsgemeinschaft (Pi 159/9), a GRF grant from the Research Grants Council of Hong Kong (No. CUHK480709), a fund from the Key Project of Knowledge Innovation Program of the Chinese Academy of Sciences (KSCX2-YW-R-083), and the Intramural Research Program of the National Institute of Child Health and Human Development, NIH.

Author contact:

CHEN Yonglong, Ph.D.

Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China

E-mail: chen_yonglong@gibh.ac.cn