The rat is immature at birth and undergoes major developmental changes at the end of the suckling period. This review deals with the maturation of ingestive behavior, gastrointestinal digestive and absorptive functions, liver metabolism, and brain structure and function. Each aspect of development is physiologically correlated with the dietary transition of weaning. However, it is unlikely that the process of weaning acts as a cue for the ontogenic changes. In contrast, there is strong evidence for an important role of both thyroxine and corticosterone as coordinators of maturational events in various organ systems.

SUMMARY The canonical Wnt/β-catenin signaling pathway governs diverse developmental, homeostatic and pathologic processes. Palmitoylated Wnt ligands engage cell surface Frizzled (Fzd) receptors and Lrp5/6 co-receptors enabling β-catenin nuclear translocation and Tcf/Lef-dependent gene transactivation1–3. Mutations in Wnt downstream signaling components have revealed diverse functions presumptively attributed to Wnt ligands themselves, although direct attribution remains elusive, as complicated by redundancy between 19 mammalian Wnts and 10 Fzds1 and Wnt hydrophobicity2,3. For example, individual Wnt ligand mutations have not revealed homeostatic phenotypes in the intestinal epithelium4, an archetypal canonical Wnt pathway-dependent rapidly self-renewing tissue whose regeneration is fueled by proliferative crypt Lgr5+ intestinal stem cells (ISCs)5–9. R-spondin ligands (Rspo1–4) engage distinct Lgr4-6 and Rnf43/Znrf3 receptor classes10–13, markedly potentiate canonical Wnt/β-catenin signaling and induce intestinal organoid growth in vitro and Lgr5+ ISCs in vivo8,14–17. However, the interchangeability, functional cooperation and relative contributions of Wnt versus Rspo ligands to in vivo canonical Wnt signaling and ISC biology remain unknown. Here, we deconstructed functional roles of Wnt versus Rspo ligands in the intestinal crypt stem cell niche. We demonstrate that the default fate of Lgr5+ ISCs is lineage commitment, escape from which requires both Rspo and Wnt ligands. However, gain-of-function studies using Rspo versus a novel non-lipidated Wnt analog reveal qualitatively distinct, non-interchangeable roles for these ligands in ISCs. Wnts are insufficient to induce Lgr5+ ISC self-renewal, but rather confer a basal competency by maintaining Rspo receptor expression that enables Rspo to actively drive and specify the extent of stem cell expansion. This functionally non-equivalent yet cooperative interplay between Wnt and Rspo ligands establishes a molecular precedent for regulation of mammalian stem cells by distinct priming and self-renewal factors, with broad implications for precision control of tissue regeneration.

SUMMARY Several cell populations have been reported to possess intestinal stem cell (ISC) activity during homeostasis and injury-induced regeneration. Here, we explored inter-relationships between putative mouse ISC populations by comparative RNA-sequencing (RNA-seq). The transcriptomes of multiple cycling ISC populations closely resembled Lgr5+ ISCs, the most well-defined ISC pool, but Bmi1-GFP+ cells were distinct and enriched for enteroendocrine (EE) markers including Prox1. Prox1-GFP+ cells exhibited sustained clonogenic growth in vitro, and lineage-tracing of Prox1+ cells revealed long-lived clones during homeostasis and after radiation-induced injury in vivo. Single-cell mRNA-seq revealed two subsets of Prox1-GFP+ cells, one of which resembled mature EE cells while the other displayed low level EE gene expression but co-expressed tuft cell markers, Lgr5 and Ascl2, reminiscent of label-retaining secretory progenitors. Our data suggest that the EE lineage, including mature EE cells, comprise a reservoir of homeostatic and injury-inducible ISCs, extending our understanding of cellular plasticity and stemness.

A sensitive protein-binding assay has been used to measure plasma concentrations of total corticosterone during postnatal development in the rat. These concentrations were extremely low on days 6--12, showed a significant rise by day 14, and then continued to rise until peaking on day 24. Plasma titers of corticosteroid-binding globulin rose even more dramatically from day 12 onward. Consequently, the percentage of total plasma corticosterone, which was protein-bound, showed a gradual rise from 78% on day 12 to 98% on day 24. Despite this trend, when concentrations of free corticosterone were calculated, they were found to have a developmental profile very similar to that of total corticosterone. Assay of jejunal lactase and sucrase in the same animals that were used for the corticosterone studies showed that the ontogenic rise of both total and free corticosterone preceded the developmental changes in the activities of these enzymes by approximately 2 days. The data suggest that the rise in free corticosterone that begins on day 14 acts as a cue for enzymic changes in both liver and intestine.

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