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Cell proliferation is tightly controlled by inhibitors that block cell cycle progression until growth signals relieve this inhibition, allowing cells to divide. In several tissues, including the liver, cell proliferation is inhibited at mitosis by the transcriptional repressors E2F7 and E2F8, leading to formation of polyploid cells. Whether growth factors promote mitosis and cell cycle progression by relieving the E2F7/E2F8-mediated inhibition is unknown. We report here on a mechanism of cell division control in the postnatal liver, in which Wnt/β-catenin signaling maintains active hepatocyte cell division throughTbx3, a Wnt target gene. The TBX3 protein directly represses transcription ofE2f7andE2f8, thereby promoting mitosis. This cascade of sequential transcriptional repressors, initiated by Wnt signals, provides a paradigm for exploring how commonly active developmental signals impact cell cycle completion.

Nutrient availability fluctuates in most natural populations, forcing organisms to undergo periods of fasting and re-feeding. It is unknown how dietary change influences cell proliferation in the liver. Here, we show that intermittent fasting (IF) promotes rapid hepatocyte proliferation. Mechanistically, IF elicits intestinal production of endocrine FGF15, which activates the {beta}-KLOTHO receptor on hepatocytes to induce proliferation. Furthermore, IF-induced proliferation is locally controlled in hepatocytes by WNT signaling and the WNT target gene Tbx3. IF induces hepatocyte proliferation to re-establish a constant liver-to-body-mass ratio during periods of fasting and re-feeding and maintain the hepatostat. This study provides the first example of dietary influence on adult hepatocyte proliferation and identifies both systemic FGF and local WNT as regulators of this process.

Cell proliferation is tightly controlled by inhibitors that block cell cycle progression until growth signals relieve this inhibition. In several tissues including the liver, transcriptional repressors such as E2F7 and E2F8 function as inhibitors of mitosis and promote polyploidy, but how growth factors release these mitotic inhibitors to facilitate cell cycle progression is unknown. We describe here a newly identified mechanism of cell division control in which Wnt/βcatenin signaling in the postnatal liver maintains active hepatocyte proliferation through Tbx3, a Wnt target gene. TBX3 directly represses transcription of E2f7 and E2f8, promoting a low ploidy state and cell cycle progression. This sequential transcriptional repressor cascade, initiated by Wnts, provides a new paradigm for exploring how a commonly active developmental signal impacts cell cycle completion.

Although most nephron segments contain one type of epithelial cell, the collecting ducts consists of at least two: intercalated (IC) and principal (PC) cells, which regulate acid-base and salt-water homeostasis, respectively. In adult kidneys, these cells are organized in rosettes suggesting functional interactions. Genetic studies in mouse revealed that transcription factor Tfcp2l1 coordinates IC and PC development. Tfcp2l1 induces the expression of IC specific genes, including specific H+-ATPase subunits and Jag1. Jag1 in turn, initiates Notch signaling in PCs but inhibits Notch signaling in ICs. Tfcp2l1 inactivation deletes ICs, whereas Jag1 inactivation results in the forfeiture of discrete IC and PC identities. Thus, Tfcp2l1 is a critical regulator of IC-PC patterning, acting cell-autonomously in ICs, and non-cell-autonomously in PCs. As a result, Tfcp2l1 regulates the diversification of cell types which is the central characteristic of 'salt and pepper' epithelia and distinguishes the collecting duct from all other nephron segments.

The Sox family of transcription factors are well-established regulators of cell fate decisions during development. Accumulating evidence documents that they play additional roles in adult tissue homeostasis and regeneration. Remarkably, forced expression of Sox factors, in combination with other synergistic factors, reprograms differentiated cells into somatic or pluripotent stem cells. Dysregulation of Sox factors has been further implicated in diseases including cancer. Here, we review molecular and functional evidence linking Sox proteins with stem cell biology, cellular reprogramming, and disease with an emphasis on Sox2.

Although most nephron segments contain one type of epithelial cell, the collecting ducts consists of at least two: intercalated (IC) and principal (PC) cells, which regulate acid-base and salt-water homeostasis, respectively. In adult kidneys, these cells are organized in rosettes suggesting functional interactions. Genetic studies in mouse revealed that transcription factor Tfcp2l1 coordinates IC and PC development. Tfcp2l1 induces the expression of IC specific genes, including specific H+-ATPase subunits and Jag1. Jag1 in turn, initiates Notch signaling in PCs but inhibits Notch signaling in ICs. Tfcp2l1 inactivation deletes ICs, whereas Jag1 inactivation results in the forfeiture of discrete IC and PC identities. Thus, Tfcp2l1 is a critical regulator of IC-PC patterning, acting cell-autonomously in ICs, and non-cell-autonomously in PCs. As a result, Tfcp2l1 regulates the diversification of cell types which is the central characteristic of 'salt and pepper' epithelia and distinguishes the collecting duct from all other nephron segments. DOI: http://dx.doi.org/10.7554/eLife.24265.001

Unchecked accumulation of reactive oxygen species (ROS) compromises maintenance of hematopoietic stem cells. Regulation of ROS by the tumor suppressor protein ataxia telangiectasia mutated (ATM) is critical for preserving the hematopoietic stem cell pool. In this study we demonstrate that the Foxo3 member of the Forkhead Box O (FoxO) family of transcription factors is essential for normal ATM expression. In addition, we show that loss of Foxo3 leads to defects in hematopoietic stem cells, and these defects result from an overaccumulation of ROS. Foxo3 suppression of ROS in hematopoietic stem cells is mediated partly by regulation of ATM expression. We identify ROS-independent modulations of ATM and p16(INK4a) and ROS-mediated activation of p53/p21(CIP1/WAF1/Sdi1) tumor suppressor pathways as major contributors to Foxo3-null hematopoietic stem cells defects. Our studies demonstrate that Foxo3 represses ROS in part via regulation of ATM and that this repression is required for maintenance of the hematopoietic stem cell pool.

There now is evidence that many of the synthetic chemicals released into the environment can impact on the function of the endocrine system of many organisms. One group of chemicals, the alkylphenols, used in paints, pesticides, herbicides, detergents, and plastics, has been found to have the ability to bind estrogen receptors. This estrogenic property makes these compounds potentially hazardous to the developing reproductive system and neuroendocrine brain. In this study we determined the effects of exposure to the environmental toxins 4-nonylphenol (NP) and 4-tert-octylphenol (OP) and to synthetic estrogen diethylstilbesterol (DES) during the early postnatal period (d 0–10) on the development of reproductive function. The day of vaginal opening, ovulation, prepubertal LH levels, LH response to estradiol, estrous cyclicity, and ovarian histology were determined. In the OP- and DES-treated groups, the vaginal opening was observed to have occurred several days prior to that of the control group. The NP-treated group showed vaginal opening at ages similar to those of the control group. Treatment with OP prevented ovulation in a significant number of animals, as well as in all animals treated with DES, whereas the control and NP-treated animals ovulated normally. Animals treated with DES and OP had significantly lower ovarian weights and higher uterine weights than either control animals or NP-treated animals. Higher basal LH levels, as well as the absence of the prepubertal LH surge, were observed in both DES- and OP-treated animals. A significant number of OP-treated animals showed no LH response to the estradiol-17β challenge. NP-treated animals responded positively to the estradiol-17β challenge. Persistent estrus was also apparent in both OP- and DES-treated animals. Upon histological examination, the ovaries in OP-treated animals were found to have a decreased number of corpora lutea and an increased number of preantral and atretic follicles. These data suggest that exposure to OP during the critical period of sexual brain differentiation affects the onset of puberty and reproductive development.

Throughout life, adult organs continually adapt to variable environmental factors. Adaptive mechanisms must fundamentally differ from homeostatic maintenance, but little is known about how physiological factors elicit tissue remodeling. Here, we show that specialized stem cell responses underlie the adaptive resizing of a mature organ. In the adult Drosophila midgut, intestinal stem cells interpret a nutrient cue to ‘break homeostasis’ and drive growth when food is abundant. Activated in part by niche production of insulin, stem cells direct a growth program through two altered modes of behavior: accelerated division rates and predominance of symmetric division fates. Together, these altered modes produce a net increase in total intestinal cells, which is reversed upon withdrawal of food. Thus, tissue renewal programs are not committed to maintain cellular equilibrium; stem cells can remodel organs in response to physiological triggers.

In the embryonic kidney, progenitors in the metanephric mesenchyme differentiate into specialized renal epithelia in a defined sequence characterized by the formation of cellular aggregates, conversion into polarized epithelia and segmentation along a proximal-distal axis. This sequence is reiterated throughout renal development to generate nephrons. Here, we identify global transcriptional programs associated with epithelial differentiation utilizing an organ culture model of rat metanephric mesenchymal differentiation, which recapitulates the hallmarks of epithelialization in vivo in a synchronized rather than reiterative fashion. We observe activation of multiple putative targets ofβ-catenin/TCF/Lef-dependent transcription coinciding with epithelial differentiation. We show in cultured explants that isolated activation ofβ-catenin signaling in epithelial progenitors induces, in a TCF/Lef-dependent manner, a subset of the transcripts associated with epithelialization, including Pax8, cyclin D1 (Ccnd1) and Emx2. This is associated with anti-apoptotic and proliferative effects in epithelial progenitors, whereas cells with impaired TCF/Lef-dependent transcription are progressively depleted from the epithelial lineage. In vivo,TCF/Lef-responsive genes comprise a conserved transcriptional program in differentiating renal epithelial progenitors and β-catenin-containing transcriptional complexes directly bind to their promoter regions. Thus,β-catenin/TCF/Lef-mediated transcriptional events control a subset of the differentiation-associated transcriptional program and thereby participate in maintenance, expansion and stage progression of the epithelial lineage.