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In many mammalian species, the intestinal epithelium undergoes major changes that allow a dietary transition from mother's milk to the adult diet at the end of the suckling period. These complex developmental changes are the result of a genetic programme intrinsic to the gut tube, but its regulators have not been identified. Here we show that transcriptional repressor B lymphocyte-induced maturation protein 1 (Blimp1) is highly expressed in the developing and postnatal intestinal epithelium until the suckling to weaning transition. Intestine-specific deletion of Blimp1 results in growth retardation and excessive neonatal mortality. Mutant mice lack all of the typical epithelial features of the suckling period and are born with features of an adult-like intestine. We conclude that the suckling to weaning transition is regulated by a single transcriptional repressor that delays epithelial maturation. Many mammals are born with an immature intestinal epithelium, which adapts to a changing diet during the weaning period. Muncan et al . show that the transcriptional repressor Blimp1 is expressed in the intestine of mice at birth, and that expression is lost at the transition to the weaning stage.

In 2021, the National Institutes of Health Advisory Committee to the Director (ACD) announced recommendations to improve the reproducibility of biomedical research using animals. In response, The Jackson Laboratory faculty and institutional leaders identified key strategies to further address this important issue. Taking inspiration from the evolution of clinical trials over recent decades in response to similar challenges, we identified opportunities for improvement, including establishment of common standards, use of genetically diverse populations, requirement for robust study design with appropriate statistical methods, and improvement in public databases to facilitate meta-analyses. In this Perspective, we share our response to ACD recommendations, with a specific focus on mouse models, with the aim of promoting continued active dialogue among researchers, using any animal system, worldwide. Such discussion will help to inform the biomedical community about these recommendations and further support their much-needed implementation.

Background and aimsThe transcription factor GATA4 is expressed throughout most of the small intestine except distal ileum, and restricts expression of the apical sodium-dependent bile acid transporter (ASBT), the rate-limiting intestinal bile acid transporter, to distal ileum. The hypothesis was tested that reduction of GATA4 activity in mouse small intestine results in an induction of bile acid transport in proximal small intestine sufficient to restore bile acid absorption and homeostasis after ileocaecal resection (ICR).MethodsBile acid homeostasis was characterised in non-surgical, sham or ICR mice using two recombinant Gata4 models in which Asbt expression is induced to different levels.ResultsReduction of intestinal GATA4 activity resulted in an induction of ASBT expression, bile acid absorption and expression of bile acid-responsive genes in proximal small intestine, and a reduction of luminal bile acids in distal small intestine. While faecal bile acid excretion and bile acid pool size remained unchanged, the bile acid pool became more hydrophilic due to a relative increase in tauro-β-muricholate absorption. Furthermore, proximal induction of Asbt in both Gata4 mutant models corrected ICR-associated bile acid malabsorption, reversing the decrease in bile acid pool size and increase in faecal bile acid excretion and hepatic cholesterol 7α-hydroxylase expression.ConclusionsReduction of intestinal GATA4 activity induces bile acid absorption in proximal small intestine without inducing major changes in bile acid homeostasis. This induction is sufficient to correct bile acid malabsorption caused by ICR in mice.

Background GATA transcription factors are essential for self-renewal of the small intestinal epithelium. Gata4 is expressed in the proximal 85% of small intestine while Gata6 is expressed throughout the length of small intestine. Deletion of intestinal Gata4 and Gata6 results in an altered proliferation/differentiation phenotype, and an up-regulation of SAM pointed domain containing ETS transcription factor ( Spdef ), a transcription factor recently shown to act as a tumor suppressor. The goal of this study is to determine to what extent SPDEF mediates the downstream functions of GATA4/GATA6 in the small intestine. The hypothesis to be tested is that intestinal GATA4/GATA6 functions through SPDEF by repressing Spdef gene expression. To test this hypothesis, we defined the functions most likely regulated by the overlapping GATA6/SPDEF target gene set in mouse intestine, delineated the relationship between GATA6 chromatin occupancy and Spdef gene regulation in Caco-2 cells, and determined the extent to which prevention of Spdef up-regulation by Spdef knockout rescues the GATA6 phenotype in conditional Gata6 knockout mouse ileum. Results Using publicly available profiling data, we found that 83% of GATA6-regulated genes are also regulated by SPDEF, and that proliferation/cancer is the function most likely to be modulated by this overlapping gene set. In human Caco-2 cells, GATA6 knockdown results in an up-regulation of Spdef gene expression, modeling our mouse Gata6 knockout data. GATA6 occupies a genetic locus located 40 kb upstream of the Spdef transcription start site, consistent with direct regulation of Spdef gene expression by GATA6. Prevention of Spdef up-regulation in conditional Gata6 knockout mouse ileum by the additional deletion of Spdef rescued the crypt cell proliferation defect, but had little effect on altered lineage differentiation or absorptive enterocytes gene expression. Conclusion SPDEF is a key, immediate downstream effecter of the crypt cell proliferation function of GATA4/GATA6 in the small intestine.

Background and Aim The regulation of human intestinal lactase-phlorizin hydrolase remains incompletely understood. One kb of pig and 2 kb of rat 5′-flanking sequence controls correct tissue, cell, topographic, and villus LCT expression. To gain insight into human LCT expression, transgenic mouse lines were generated from 3.3 kb of human LPH 5′ flanking sequence from a lactase persistent individual fused to a human growth hormone (hGH) reporter bounded by an insulator. Methods Four lines were identified in which reporter expression was specifically detectable in the intestine and no other organ, two of which demonstrated hGH expression specific to small and large intestine. Quantitative RT-PCR was carried out on proximal to distal segments of small intestine at fetal days 16.5 and 18.5 and at birth, postnatal days 7 and 28 in line 22. Results In fetal intestine, hGH expression demonstrated a proximal to distal gradient similar to that in native intestine. There was no significant difference between hGH expression levels at 7 and 28 days in segment 3, the midpoint of the small intestine, where expression of endogenous lactase is maximal at 7 days and declines significantly by 28 days. Distal small intestine displayed high levels of hGH expression in enteroendocrine cells, which were shown to be a subset of the PYY cells. Conclusions Thus, a 3.3-kb LPH 5′ flanking sequence construct from a lactase persistent individual is able to maintain postnatal expression in transgenic mice post weaning.

Human adult-onset lactase decline is a biologic feature characteristic of the maturing intestine in the majority of the world's population. The digestion and absorption of lactose, the major carbohydrate in milk and also the main substrate for lactase, is often variable, a consequence of lactase levels, gastric emptying rate, and colonic salvage. Although commercially available \"lactase\" products alleviate symptoms in many lactose-intolerant people, a greater understanding of this variability in lactose tolerance could lead to interventions that reduce the rate of gastric emptying and/or increase the proliferation of lactose-metabolizing bacteria in the colon, leading to more efficient lactose utilization. Adult-onset lactase decline appears to be a risk factor for developing osteoporosis, owing to avoidance of dairy products or interference of undigested lactose with calcium absorption. Elderly with both adult-onset lactase decline and atrophic gastritis or those undergoing anti-ulcer treatment may have an increased risk of low calcium absorption owing to the lack of gastric acid that facilitates calcium uptake. Thus, lactose-intolerant elders should monitor their calcium nutrition status carefully

GATA transcription factors are essential for self-renewal of the small intestinal epithelium. Gata4 is expressed in the proximal 85% of small intestine while Gata6 is expressed throughout the length of small intestine. Deletion of intestinal Gata4 and Gata6 results in an altered proliferation/differentiation phenotype, and an up-regulation of SAM pointed domain containing ETS transcription factor (Spdef), a transcription factor recently shown to act as a tumor suppressor. The goal of this study is to determine to what extent SPDEF mediates the downstream functions of GATA4/GATA6 in the small intestine. The hypothesis to be tested is that intestinal GATA4/GATA6 functions through SPDEF by repressing Spdef gene expression. To test this hypothesis, we defined the functions most likely regulated by the overlapping GATA6/SPDEF target gene set in mouse intestine, delineated the relationship between GATA6 chromatin occupancy and Spdef gene regulation in Caco-2 cells, and determined the extent to which prevention of Spdef up-regulation by Spdef knockout rescues the GATA6 phenotype in conditional Gata6 knockout mouse ileum. Using publicly available profiling data, we found that 83% of GATA6-regulated genes are also regulated by SPDEF, and that proliferation/cancer is the function most likely to be modulated by this overlapping gene set. In human Caco-2 cells, GATA6 knockdown results in an up-regulation of Spdef gene expression, modeling our mouse Gata6 knockout data. GATA6 occupies a genetic locus located 40 kb upstream of the Spdef transcription start site, consistent with direct regulation of Spdef gene expression by GATA6. Prevention of Spdef up-regulation in conditional Gata6 knockout mouse ileum by the additional deletion of Spdef rescued the crypt cell proliferation defect, but had little effect on altered lineage differentiation or absorptive enterocytes gene expression. SPDEF is a key, immediate downstream effecter of the crypt cell proliferation function of GATA4/GATA6 in the small intestine.

Background and Aim: The regulation of human intestinal lactase-phlorizin hydrolase remains incompletely understood. One kb of pig and 2kb of rat 5'-flanking sequence controls correct tissue, cell, topographic, and villus LCT expression. To gain insight into human LCT expression, transgenic mouse lines were generated from 3.3kb of human LPH 5' flanking sequence from a lactase persistent individual fused to a human growth hormone (hGH) reporter bounded by an insulator. Methods: Four lines were identified in which reporter expression was specifically detectable in the intestine and no other organ, two of which demonstrated hGH expression specific to small and large intestine. Quantitative RT-PCR was carried out on proximal to distal segments of small intestine at fetal days 16.5 and 18.5 and at birth, postnatal days 7 and 28 in line 22. Results: In fetal intestine, hGH expression demonstrated a proximal to distal gradient similar to that in native intestine. There was no significant difference between hGH expression levels at 7 and 28days in segment 3, the midpoint of the small intestine, where expression of endogenous lactase is maximal at 7days and declines significantly by 28days. Distal small intestine displayed high levels of hGH expression in enteroendocrine cells, which were shown to be a subset of the PYY cells. Conclusions: Thus, a 3.3-kb LPH 5' flanking sequence construct from a lactase persistent individual is able to maintain postnatal expression in transgenic mice post weaning.

3 groups of high-risk newborns and their controls were assessed at 92 weeks post-conceptional age using Bayley's Infant Behavioral Record (IBR). The 3 groups of high-risk infants were those who weighed 1,500 grams or less at birth and required no ventilator therapy, those weighing 1,500 grams or less at birth who required ventilator therapy, and newborns weighing more than 1,500 grams at birth who required ventilator therapy. Controls were healthy term infants matched for 7 socioeconomic and demographic variables. The first principal component of the IBR ratings for the 3 groups of high-risk infants and the controls were similar. All 3 groups of high-risk infants received less desirable IBR ratings on most items than their controls. In addition, there were some differences among high-risk groups; ventilated infants regardless of birth weight received the lowest ratings reflecting overall performance on the IBR, very low birth-weight, ventilated newborns were more likely to receive ratings characterizing an overly active infant with a short attention span, and very low birth-weight, never-ventilated infants were most likely to be rated as happy but passive and delayed. The differences between the high-risk infants and controls in large part resulted from infants who were also delayed in terms of their mental and motor development.

At 92 weeks postconceptual age, 192 high-risk infants with birth weights ≤ 1,500 grams and/or requiring ventilator support shortly after birth, and 85 full-term infants who were healthy newborns, were administered the Bayley Scales of Infant Development. A principal component analysis was performed separately for the high-risk and control infants. There was a reasonable degree of congruence between the first principal component for the high-risk infants and that of the controls, although the first principal component of the high-risk infants explained a greater number of heavily weighted items than for the control infants. The similarity was increased when differences in developmental levels were controlled for. There was considerable similarity between the results of analyses for high-risk infants and those for normal infants reported in the literature.