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The Transcriptional Repressor Blimp1/Prdm1 Regulates Postnatal Reprogramming of Intestinal Enterocytes

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The Transcriptional Repressor Blimp1/Prdm1 Regulates Postnatal Reprogramming of Intestinal Enterocytes The transcriptional repressor Blimp1/Prdm1 regulates postnatal reprogramming of intestinal enterocytes James Harpera, Arne Moulda, Robert M. Andrewsb, Elizabeth K. Bikoffa, and Elizabeth J. Robertsona,1 aSir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom; and bWellcome Trust Sanger Institute, Genome Campus, Hinxton-Cambridge CB10 1SA, United Kingdom Edited by Brigid L. M. Hogan, Duke University Medical Center, Durham, NC, and approved May 19, 2011 (received for review April 13, 2011) Female mammals produce milk to feed their newborn offspring rise to the developing crypts. The crypt derived adult enterocytes before teeth develop and permit the consumption of solid food. that emerge at postnatal day (P) 12 and repopulate the entire Intestinal enterocytes dramatically alter their biochemical signature epithelium lack Blimp1 expression. Conditional inactivation of during the suckling-to-weaning transition. The transcriptional re- Blimp1 results in globally misregulated gene expression patterns, pressor Blimp1 is strongly expressed in immature enterocytes in and compromises small intestine (SI) tissue architecture, nutrient utero, but these are gradually replaced by Blimp1− crypt-derived uptake, and survival of the neonate. In combination with tran- adult enterocytes. Here we used a conditional inactivation strategy scriptional profiling, the present experiments demonstrate that to eliminate Blimp1 function in the developing intestinal epithe- Blimp1/Prdm1 orchestrates orderly and extensive reprogramming lium. There was no noticeable effect on gross morphology or of the postnatal intestinal epithelium. formation of mature cell types before birth. However, survival of mutant neonates was severely compromised. Transcriptional Results profiling experiments reveal global changes in gene expression Down-Regulated Blimp1 Expression in Crypt Progenitors Beginning at patterns. Key components of the adult enterocyte biochemical sig- Birth. Blimp1 is strongly expressed throughout the embryonic gut nature were substantially and prematurely activated. In contrast, endoderm (8, 12). Expression is maintained in the fetal SI those required for processing maternal milk were markedly re- throughout development (Fig. 1A), but, beginning at birth, the + duced. Thus, we conclude Blimp1 governs the developmental pattern dramaticallychanges. Expression islost in a subset ofc-Myc switch responsible for postnatal intestinal maturation. cells within the intervillus pockets. During the next 10 to 12 d, this population expands to form the mature crypts (Fig. 1A). In striking enterocyte maturation | gut development | nutrition | cell fate contrast, immature enterocytes retain Blimp1 expression (Fig. 1A). Slightly later Blimp1+ cells shift distally, and by P18 expression is strictly confined to the luminal villus tips (Fig. 1A). From post- he defining characteristic of placental mammals is the presence weaning onward, the intestinal epithelium lacks Blimp1 expression. of highly specialized mammary glands that secrete milk. During T Next, we compared cell proliferation (by Ki67 labeling) and the suckling phase, neonates rely entirely on a lactose-rich milk diet. Blimp1 expression during formation of the crypt villus axis (Fig. BIOLOGY Immature enterocytes are highly specialized for pinocytosis and 1B). At E16.5, expression colocalizes to the intervillus pockets and processing of milk constituents. During the suckling-to-weaning fi DEVELOPMENTAL transition, as teeth develop enabling consumption of solid foods high proximal villus. Signi cant numbers of double-positive cells are in sucrose and maltose, intestinal enzymatic pathways adapt ap- retained at P2 in the proximal villi, but the percentage decreases propriately to mediate efficient carbohydrate breakdown. The reg- during the next few days. A few double-positive cells persist at P10, but are subsequently lost. From P14 onward, Blimp1+ en- ulatory mechanisms responsible for controlling this developmental − switch in enterocyte gene expression profiles remain unknown. terocytes are rapidly displaced as mature Blimp1 enterocytes The mouse gut tube is initially comprised of a pseudostratified emerge from the crypts and migrate up the villus axis. In contrast, fi Ki67+ cells are strictly confined to the crypts. To confirm that layer of de nitive endoderm surrounded by splanchnic mesoderm. − + Starting at approximately embryonic day (E) 14.5, the mesen- Blimp1 adult crypt stem cells derive from Blimp1 fetal pro- chyme begins to invaginate into the endoderm to form the finger- genitors, Blimp1.Cre transgenic mice (6) were crossed to the R26R like villi that protrude into the luminal space. Formation of ter- reporter strain (13) and stained for LacZ activity at P36. As minally differentiated cell types including absorptive enterocytes, expected, LacZ-positive crypts as well as labeled progeny were mucus secreting goblet cells, and enteroendocrine cells proceeds detectable along the entire villus axis (Fig. S1). from E14.5 onward. Subsequent growth of the epithelial sheet is driven by proliferative cells restricted to the intervillus pockets Conditional Inactivation Results in Postnatal Lethality. We crossed the Villin.Cre transgenic strain that expresses Cre in yolk sac and (1). Starting at birth, their derivatives migrate into the underlying CA/CA mesenchyme to generate the intestinal crypts. In the adult in- gut endoderm from E12.5 onward (14) to Prdm1 animals testine, stem cells at the base of the crypts proliferate continuously (15) to selectively eliminate Blimp1 functions in the developing CA/CA to replace epithelial cells being shed from the villus tips (2). SI. As expected in Villin.Cre;Prdm1 embryos (referred to as The transcriptional repressor Blimp1, encoded by the Prdm1 Blimp1 mutants), expression in the intestinal epithelium was gene, contains an N-terminal PR/SET domain and five C-terminal C2H2 zinc fingers that mediate nuclear import and DNA binding (3). Originally identified as a silencer of β-IFN gene expression (4), Author contributions: J.H., E.K.B., and E.J.R. designed research; J.H. and E.J.R. performed and a master regulator of plasma cell differentiation (5), Blimp1 research; J.H., A.M., R.M.A., and E.J.R. analyzed data; and E.K.B. and E.J.R. wrote the acts downstream of Bmp/Smad signals in the early embryo to si- paper. lence the default somatic pathway and specify primordial germ cells The authors declare no conflict of interest. (6, 7). Blimp1 also regulates development of the posterior forelimb, This article is a PNAS Direct Submission. caudal pharyngeal arches, and sensory vibrissae (8), and governs Freely available online through the PNAS open access option. fi gene expression pro les in T-cell subsets (9), the sebaceous gland Data deposition. Array data reported in this paper have been deposited in the Gene (10), and skin epidermis (11). Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. Here we report that Blimp1 acts as a master regulator of in- GSE29658). testinal maturation. Blimp1 is strongly expressed throughout the 1To whom correspondence should be addressed. E-mail: [email protected]. epithelium of the embryonic gut. Beginning at birth, expression This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. becomes down-regulated in the subset of intervillus cells that give 1073/pnas.1105852108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1105852108 PNAS | June 28, 2011 | vol. 108 | no. 26 | 10585–10590 Downloaded by guest on September 27, 2021 Fig. 2. Blimp1 inactivation fails to disturb intestinal morphogenesis before birth. (A–H) Conditional loss of Blimp1 has no noticeable effect on expres- sion of mature markers of enterocyte (alkaline phosphatase), goblet (mucin- 2), and enteroendocrine cells (chromogranin), or Sox9, a marker of Paneth cell progenitors. (I–K) More than 20 completely intact villi from proximal sections stained for phosphohistone 3, mucin 2, or chromogranin were counted (box, interquartile range; horizontal line, median; vertical line, minimum to maximum values excluding outliers; cross, mean). ever, compared with control littermates, these pups are growth- retarded, and nearly half(P = 0.0001) died within 10 d of birth (Fig. 3 A and B). The SI tissue architecture was clearly disturbed (Fig. 3 C–H and Fig. S3). Villus density was reduced. Moreover, intervillous cells were highly vacuolated, retained only patchy Ki67/c-Myc expression, and strongly expressed the enterocyte marker alkaline phosphatase at the apical surface, a phenotype consistent with premature ter- minal differentiation. Interestingly, in Tcf4-deficientembryos, loss of Wnt-mediated proliferation similarly results in failure to maintain the intervillus stem cell compartment and causes cells to acquire a terminal columnar phenotype starting at E16.5 (22). The SI of adult survivors invariably contains both WT and LacZ- Fig. 1. Dynamic Blimp1 expression patterns during intestinal maturation. (A) marked deleted cells (Fig. S3). Thus, the incompletely penetrant + At E16.5, c-Myc cells are restricted to the intervillus pockets but become con- phenotype is caused by a few exceptional WT cells that escape fined to developing crypts from P0 onward. Blimp1 is broadly expressed − excision during embryogenesis and rapidly expand postnatally to throughout the fetal endoderm. At P0, individual Blimp1 cells are detectable support villus homeostasis. However, the initial weight loss ob- within the intervillus
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