PAR-4/LKB1 regulates intestinal cell number by restricting endoderm specification to the E lineage

The master kinase PAR-4/LKB1 appears as a major regulator of intestinal physiology. It is in particular mutated in the Peutz-Jeghers syndrome, an inherited disorder in which patients develop benign intestine polyps. Moreover, ectopic activation of PAR-4/LKB1 is sufficient to induce the polarized accumulation of apical and basolateral surface proteins and the formation of apical microvilli-like structures in intestinal epithelial cancer cell lines. In C. elegans, PAR-4 was shown to be required for the differentiation of intestinal cells. Here, we further examine the role of PAR-4 during intestinal development. We find that it is not required for the establishment of enterocyte polarity and plays only a minor role in brush border formation. By contrast, par-4 mutants display severe deformations of the intestinal lumen as well as supernumerary intestinal cells, thereby revealing a novel function of PAR-4 in preventing intestinal hyperplasia. Importantly, we find that the ability of PAR-4 to control intestinal cell number does not involve the regulation of cell proliferation but is rather due to its ability to restrict the expression of intestinal cell fate factors to the E blastomere lineage. We therefore propose that PAR-4 is required to regulate C. elegans intestine specification.