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Defining Pancreatic Endocrine Precursors and Their Descendants Peter White,1 Catherine Lee May,1,2 Rodrigo N

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Defining Pancreatic Endocrine Precursors and Their Descendants Peter White,1 Catherine Lee May,1,2 Rodrigo N ORIGINAL ARTICLE Defining Pancreatic Endocrine Precursors and Their Descendants Peter White,1 Catherine Lee May,1,2 Rodrigo N. Lamounier,1 John E. Brestelli,1 and Klaus H. Kaestner1 OBJECTIVE—The global incidence of diabetes continues to The Edmonton cadaveric islets transplantation protocol increase. Cell replacement therapy and islet transplantation offer (4) opened the door to improved treatment of the disease hope, especially for severely affected patients. Efforts to differ- but faces two significant challenges: the need for improved entiate insulin-producing ␤-cells from progenitor or stem cells immuno-regulatory measures and the necessity to increase require knowledge of the transcriptional programs that regulate the supply of islets or ␤-cells by a factor of at least 1,000 to the development of the endocrine pancreas. be able to treat even the most severely affected patients. RESEARCH DESIGN AND METHODS—Differentiation to- While we have gained significant insights into the tran- ward the endocrine lineage is dependent on the transcription scriptional programs and signaling mechanisms that con- factor Neurogenin 3 (Neurog3, Ngn3). We utilize a Neurog3– trol the differentiation of endocrine precursors to mature enhanced green fluorescent protein knock-in mouse model to hormone-expressing endocrine cells of the islet (rev. in isolate endocrine progenitor cells from embryonic pancreata 5–9), efforts to direct differentiation of various cells into (embryonic day [E]13.5 through E17.5). Using advanced genomic ␤ approaches, we generate a comprehensive gene expression pro- -cells have met with only limited success (2). file of these progenitors and their immediate descendants. Differentiation of the pancreatic endocrine lineage is dependent on Neurogenin 3 (Neurog3, Ngn3), a member of RESULTS—A total of 1,029 genes were identified as being the family of basic helix-loop-helix (bHLH) transcription temporally regulated in the endocrine lineage during fetal devel- factors. Neurog3-null pancreata lack all five mature endo- opment, 237 of which are transcriptional regulators. Through crine cell types (10,11), and Neurog3 is also required for pathway analysis, we have modeled regulatory networks involv- ing these proteins that highlight the complex transcriptional enteroendocrine cell development in the stomach and hierarchy governing endocrine differentiation. intestine (12,13). Notably, regulatory genes marking endo- crine precursors, including Pax4, Pax6, Isl1, and Neurod1 CONCLUSIONS—We have been able to accurately capture the (14,15), are not expressed in the absence of Neurog3. gene expression profile of the pancreatic endocrine progenitors Ectopic expression of Neurog3 can initiate differentiation and their descendants. The list of temporally regulated genes of endocrine cells in mouse (16), humans (17), and pig identified in fetal endocrine precursors and their immediate descendants provides a novel and important resource for devel- (18). Furthermore, lineage tracing during mouse embryo- opmental biologists and diabetes researchers alike. Diabetes genesis has revealed that Neurog3-positive cells differen- 57:654–668, 2008 tiate exclusively into islet cells, suggesting that expression of this gene could be used as a marker for isolating these progenitors for further study (19). During pancreatic development in the mouse, expres- ignificant efforts to treat and potentially cure sion of Neurog3 is initiated during pancreatic budding, as diabetes have been focused on generating renew- early as embryonic day (E)9.5 in the dorsal primordium able sources of insulin-producing ␤-cells from (20,21). Relatively low levels of Neurog3 expression are their progenitors to be used in transplantation maintained until E13.5, when a dramatic upregulation is S observed, marking the beginning of the second transition (1–3). This effort is motivated by the increased incidence of both type 1 and type 2 diabetes and the limited (16). Expression is believed to peak at E15.5 and then effectiveness of pharmaceutical treatments for the disease. rapidly decrease to undetectable levels in juvenile and adult islets (10). Different transcriptional regulators par- ticipate in the activation of Neurog3, including Onecut1 From the 1Department of Genetics and Institute for Diabetes, Obesity and (Hnf6) as a direct activator of its transcription and mem- Metabolism, University of Pennsylvania School of Medicine, Philadelphia, bers of the FoxA family (7,22,23). Expression of Neurog3 Pennsylvania; and the 2Department of Pathology, The Children’s Hospital of Philadelphia Abramson Research Center, University of Pennsylvania School is restricted to a relatively small population of cells of Medicine, Philadelphia, Pennsylvania. destined for the endocrine lineages (19). After differentia- Address correspondence and reprint requests to Klaus H. Kaestner, PhD, tion into hormone-expressing cells has occurred, expres- University of Pennsylvania, Medical School, Department of Genetics, 415 Curie Blvd., Philadelphia, PA 19104. E-mail: [email protected]. sion of Neurog3 ceases. This is most likely due to negative Received for publication 26 September 2007 and accepted in revised form feedback, as Neurog3 has been shown to repress its own 30 November 2007. expression (24). Homeodomain factors such as Pax4 (25) Published ahead of print at http://diabetes.diabetesjournals.org on 10 De- cember 2007. DOI: 10.2337/db07-1362. and Nkx2–2 (26) as well as the bHLH factor NeuroD1 (27) Additional information for this article can be found in an online appendix at are targets for Neurog3 activation. However, the majority http://dx.doi.org/10.2337/db07-1362. of downstream genes dependent on Neurog3 and the bHLH, basic helix-loop-helix; EDGE, Extraction of Differential Gene Ex- mechanisms through which this factor regulates differen- pression; EGFP, enhanced green fluorescent protein; GO, gene ontology; HLH, helix-loop-helix; qRT-PCR, quantitative real-time RT-PCR. tiation of endocrine precursors into islet cells are un- © 2008 by the American Diabetes Association. known. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance In the present study we set out to identify potential with 18 U.S.C. Section 1734 solely to indicate this fact. novel targets of Neurog3 and to determine the transcrip- 654 DIABETES, VOL. 57, MARCH 2008 P. WHITE AND ASSOCIATES tome of the endocrine lineage during fetal development. incubated in a Corning Hybridization chamber (Corning Incorporated Life Taking advantage of the fact that enhanced green fluores- Sciences) overnight at 42°C. The Mouse PancChip 6 contains ϳ13,000 mouse cent protein (EGFP) persists in cells for several days after cDNAs chosen for their expression in various stages of pancreatic develop- ment, many of which are not found on commercially available arrays. Detailed the promoter driving its expression has been turned off, information on this array and full protocols are available at http://www.cbi- we were able to sort Neurog3-EGFP endocrine precursors l.upenn.edu/EPConDB. After hybridization, the coverslips were removed in and their immediate descendants from fetal pancreas. By 2ϫ SSC, 0.1% SDS, and the arrays were washed for 5 min in 0.2ϫ SSC, 0.1% determining the gene expression profile of these develop- SDS at 42°C and 5 min in 0.2ϫ SSC at room temperature. The arrays were ing cell populations, we derived gene signatures that can immediately scanned with the Agilent DNA Microarray Scanner, Model be used to guide future efforts to enhance differentiation of G2565B (Agilent Technologies) at a resolution of 5 ␮mol/l. Data processing. The median Cy5 (red) and Cy3 (green) intensities of each endocrine precursors. element on the array were determined by processing the array images with GenePix Pro version 5.1 (Molecular Devices). All subsequent steps were performed using scripts we developed for this analysis in the R open-source RESEARCH DESIGN AND METHODS language environment for statistical computing (http://www.r-project.org/). Heterozygous male mice containing an EGFP-marked null allele of Neurog3 Positive control elements were removed from the dataset, and the expression (Neurog3ϩ/EGFP) (12) were mated with CD1 females and pregnant females ratio for each element on the array was calculated in terms of M [log2(red/ killed at either 12.5, 13.5, 14.5, 15.5, 16.5, or 17.5 days of gestation. Embryos green)] and A {[log2(red) ϩ log2(Green)]/2}, without local background signal were rapidly dissected and the pancreata removed and placed into PBS. subtraction. The data were normalized by the print tip loess method using the Neurog3ϩ/EGFP embryos (at the expected 50% Mendelian ratio) were easily BioConductor package “marray” (31). Quality control diagnostic plots were identified by their green fluorescence and transferred into a separate buffer prepared for each array, and those failing to exhibit high-quality hybridiza- ready for dissociation into single cells. A total of 70 pregnant females, tions were excluded from further analysis. This resulted in the final dataset producing 785 embryos, were required to produce three biological replicates containing three biological replicates for each embryonic time point and four for each time point. Adult islets were prepared from eight CD1 female mice as biological replicates for the adult islet time point, giving a total of 19 samples described previously (28). Islet preparations from two animals
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