Id2 controls specification of Lgr5+ intestinal stem cell progenitors during gut development

The adult intestinal stem cells (ISCs), their hierarchies, mechanisms of maintenance and differentiation have been extensively studied. However, when and how ISCs are established during embryogenesis remains unknown. We show here that the transcription regulator Id2 controls the specification of embryonic Lgr5 + progenitors in the developing murine small intestine. Cell fate mapping analysis revealed that Lgr5 + progenitors emerge at E13.5 in wild‐type embryos and differ from the rest on the intestinal epithelium by a characteristic ISC signature. In the absence of Id2, the intestinal epithelium differentiates into Lgr5 + cells already at E9.5. Furthermore, the size of the Lgr5 + cell pool is significantly increased. We show that Id2 restricts the activity of the Wnt signalling pathway at early stages and prevents precocious differentiation of the embryonic intestinal epithelium. Id2‐deficient embryonic epithelial cells cultured ex vivo strongly activate Wnt target genes as well as markers of neoplastic transformation and form fast growing undifferentiated spheroids. Furthermore, adult ISCs from Id2‐deficient mice display a distinct transcriptional signature, supporting an essential role for Id2 in the correct specification of ISCs. Synopsis Fate mapping and transcriptome analyses show that Id2 prevents early specification of Lgr5 + intestinal stem cells (ISCs) by blocking Wnt signalling in the murine embryonic epithelium. In absence of Id2, precocious Lgr5 + cells give rise to adult ISCs with predisposition to neoplasia. Lgr5 + precursors of adult ISCs are specified at E13.5. Id2 negatively regulates Wnt/β‐catenin signalling. Id2 controls the timing of Lgr5 + intestinal stem cell specification during embryogenesis. Id2 restricts the number of Lgr5 + progenitors in developing small intestine. Precocious Lgr5 + cells give rise to adult ISCs with altered transcriptional programme and proliferation. Graphical Abstract Transcriptional regulator Id2 prevents early specification of Lgr5 + intestinal stem cells by blocking Wnt signalling in the murine embryonic epithelium.