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The intestinal epithelium has constant turnover throughout the life of the organ, with apoptosis of cells at the tips of folds or villi releasing cells into the lumen. Due to constant turnover, epithelial cells need to be constantly replaced. Epithelial cells are supplied by stem cell niches that form at the base of the interfold space (zebrafish) and crypts (birds and mammals). Within the adult stem cell niche of mammals, secretory cells such as Paneth and goblet cells play a role in modulation of proliferation and stem cell activity, producing asymmetric divisions. Progeny of asymmetric divisions move up the fold or villi, giving rise to all of the epithelial cell types. Although much is known about function and organization of the adult intestinal stem cell niche, less is understood about regulation within the immature stem cell compartment. Following smooth muscle formation, the intestinal epithelium folds and proliferation becomes restricted to the interfold base. Symmetric divisions continue in the developing interfold niche until stem cell progeny begin asymmetric divisions, producing progeny that migrate up the developing folds. Proliferative progeny from the developing stem cell niche begin migrating out of the niche during the third week post-embryogenesis (zebrafish) or during the postnatal period (mammals). Regulation and organization of epithelial proliferation in the immature stem cell niche may be regulated by signals comparable to the adult niche. Here we identify a novel subset of secretory cells associated with the developing stem cell niche that receive Notch signaling (referred to as NRSCs). Inhibition of the embryonic NRSCs between 74 hpf to 120 hpf increases epithelial proliferation as well as EGF and IGF signaling. Inhibition of post-embryonic NRSCs (6 hpf to 12 dpf) also increases epithelial proliferation and expression level of Wnt target genes. We conclude that NRSCs play a role in modulation of epithelial proliferation through repression of signaling pathways that drive proliferation during both embryogenesis and the post embryonic period.

BACKGROUND Development of the vertebrate intestinal epithelial stem cell niche begins during embryogenesis but maturation occurs postembryonic. The intestinal mammalian crypt contains stem cells interspersed by secretory cells that play a role in regulation of proliferation. Epithelial cells are specified as either secretory or enterocytes as they migrate up the villi in mammals or fold in zebrafish. Zebrafish forms a functional intestine by the end of embryogenesis but takes another 4 weeks to develop the adult proliferation pattern. RESULTS We characterize development of the intestinal epithelial stem cell niche during the postembryonic period. During the first 2-weeks postembryogenesis, different groups of epithelial cells sequentially proceed through one or two cell cycles, appear to become quiescent, and remain at the interfold base. The third week begins asymmetric divisions with proliferative progeny moving up the folds. Apoptotic cells are not observed at the fold tip until the end of the fourth week. Secretory cells intersperse among interfold base proliferative cells, increasing in number during the third and fourth weeks with a coincident change in proliferation pattern. CONCLUSIONS Zebrafish postembryonic intestinal epithelial development consists of 2 weeks of slow proliferation followed by 2 weeks of metamorphosis to the adult structure. Developmental Dynamics 2019. © 2019 Wiley Periodicals, Inc.