SEL1L deficiency impairs growth and differentiation of pancreatic epithelial cells
© Li et al; licensee BioMed Central Ltd. 2010
Received: 17 August 2009
Accepted: 19 February 2010
Published: 19 February 2010
The vertebrate pancreas contains islet, acinar and ductal cells. These cells derive from a transient pool of multipotent pancreatic progenitors during embryonic development. Insight into the genetic determinants regulating pancreatic organogenesis will help the development of cell-based therapies for the treatment of diabetes mellitus. Suppressor enhancer lin12/Notch 1 like (Sel1l) encodes a cytoplasmic protein that is highly expressed in the developing mouse pancreas. However, the morphological and molecular events regulated by Sel1l remain elusive.
We have characterized the pancreatic phenotype of mice carrying a gene trap mutation in Sel1l. We show that Sel1l expression in the developing pancreas coincides with differentiation of the endocrine and exocrine lineages. Mice homozygous for the gene trap mutation die prenatally and display an impaired pancreatic epithelial morphology and cell differentiation. The pancreatic epithelial cells of Sel1l mutant embryos are confined to the progenitor cell state throughout the secondary transition. Pharmacological inhibition of Notch signaling partially rescues the pancreatic phenotype of Sel1l mutant embryos.
Together, these data suggest that Sel1l is essential for the growth and differentiation of endoderm-derived pancreatic epithelial cells during mouse embryonic development.
The multiple cell types that make up the adult pancreas, including endocrine, exocrine and ductal cells, derive from a common pool of pancreatic progenitors. Pancreatic development in mice begins at embryonic day 9.5 (E9.5) with the formation of two epithelial buds on the dorsal and ventral side of the primitive gut endoderm . Epithelial cells within the pancreatic buds proliferate rapidly and branch out during later embryonic days to form a complex tubular network comprised of undifferentiated multipotent progenitor cells [2, 3]. Starting at E13.5, the expanded pancreatic epithelial cells undergo an asynchronized wave of differentiation to give rise to all the differentiated cell types of the adult pancreas, including acinar cells that produce hydrolytic digestive enzymes and islet cells that secrete endocrine hormones [4, 5]. Pancreatic morphogenesis depends on a complex and yet incompletely characterized network of transcription factors. Significant efforts have been made in the past few years to understand the role of several important transcription factors, including Pdx1 [6, 7], Ptf1a [8, 9], Sox9 [10, 11]9, Ngn3 [12, 13], NeuroD1 [14, 15], Pax4 , Pax6 , Nkx2.2 , Nkx6.1 , Arx , Isl1  and Insm1 . It is generally accepted that these transcription factors coordinate pancreatic morphogenesis by functioning in concert to restrict the developmental potentials of the pancreatic progenitors in a spatial and stage-specific manner .
Several previous studies have underscored the importance of Notch-mediated signaling in regulating pancreatic cell proliferation and cell fate decisions through control of Ngn3 gene expression. During pancreatic development, Ngn3 is transiently expressed in a subset of the pancreatic epithelial cells. NGN3 deficiency completely abolishes formation of all the endocrine cell subtypes, suggesting Ngn3 functions as a master switch for the endocrine lineage in the pancreas. Mutations in genes encoding Notch signaling pathway components, such as DLL1 (ligand), RBP-Jk (the intracellular mediator), or HES-1 (the effector) causes expansion of Ngn3 expression in pancreatic cells and, as a result, accelerated differentiation of endocrine cells at the expense of acinar and ductal cells [13, 24, 25]. Conversely, over or persistent expression of the Notch intracellular domain (NICD), a constitutively active form of Notch receptors, or the Notch effector gene Hes1 results in diminished expression of Ngn3 and attenuated differentiation of endocrine cells [26–28]. These studies suggest that during pancreatic development Notch signaling controls the endocrine and exocrine cell fate decisions of pancreatic epithelial cells by directly regulating Ngn3 expression. Recent studies have also indicated the importance of Notch signaling in control of exocrine cell differentiation. Ectopic expression of activated NOTCH-1 prevents or significantly delays differentiation of acinar cells [26, 27].
While the role of Notch signaling in control of pancreatic cell proliferation and cell fate decisions is clearly recognized, the molecular mechanisms necessary for proper control of Notch signaling during vertebrate pancreatic development are poorly understood. Genetic and biochemical studies in invertebrates suggest that regulation of Notch signaling occurs at various levels and through multiple mechanisms [29–31]. These include stochastic and/or developmental expression of the Notch receptors and their ligands [32–34], selective receptor-ligand interactions [35, 36], intracellular protein trafficking  and stability of NICD . Suppressor enhancer lin12 1 like (Sel1l) encodes a cytoplasmic protein that is highly conserved throughout the vertebrate kingdom . RNA in situ hybridization and immunohistological analysis revealed that Sel1l is highly expressed in both the embryonic and adult pancreas [40–42]. The human Sel1l gene is located in a chromosome region that is in close proximity to a type 1 diabetes high risk locus, IDDM-11 (insulin-dependent diabetes mellitus locus 11), prompting the speculation that mutations in Sel1l may be associated with the pathogenesis of type 1 diabetes . Sel-1, the C. elegans ortholog of Sel1l, was first identified in a genetic screen for mutations that suppress lin-12/Notch activity . Subsequent biochemical studies demonstrated that Sel-1 negatively regulates lin-12/Notch activity by controlling lin-12/Notch turn-over [45, 46]. Based on these findings, it has been suggested that Sel1l may also function as a negative regulator for Notch signaling . Recent biochemical and molecular studies in vitro revealed that Sel1l is also required for maintaining homeostasis of the endoplasmic reticulum (ER). SEL1L nucleates an ER membrane protein complex that is required for dislocation of unfolded or misfolded proteins from the ER lumen into the cytosol for degradation [48, 49].
In an attempt to decipher the developmental and physiological roles of Sel1l, we have generated and characterized mice carrying a gene trap mutation in the Sel1l gene. We report here that Sel1l expression during pancreas development coincides with differentiation of pancreatic epithelial cells into both the endocrine and exocrine lineages. Homozygous Sel1l mutant embryos exhibit an impaired pancreatic epithelial growth and branching morphology. Pharmacological inhibition of Notch signaling rescues the pancreatic phenotype of Sel1l-deficient embryos. These data are consistent with the notion that Sel1l functions as a negative regulator for Notch signaling during pancreatic organogenesis .
Sel1l expression during mouse pancreatic development
SEL1L deficiency results in defective pancreatic epithelial growth and branching morphogenesis
SEL1L deficiency inhibits differentiation of acinar cells and significantly attenuates differentiation of endocrine cells
We next investigated the role of Sel1l in pancreatic epithelial cell differentiation. Since the first wave of cell differentiation occurs before E12.5 and the cells generated are mostly α-cells, we analyzed glucagon expression in E11.5 Sel1lβgeo/βgeoembryos. As shown in Fig. 3A-B and 3G, comparable numbers of glucagon+ cells were observed in wild-type and Sel1lβgeo/βgeoembryos. Sel1l is thus unlikely to be required for the generation of early endocrine cells during the first transition (E9.5 to E12.5).
SEL1L-deficient pancreatic epithelium exhibits inhibited growth and differentiation ex vivo
Pancreatic progenitor cells in SEL1L-deficient embryos at E15.5 are confined to a pluripotent progenitor state
Pharmacological inhibition of Notch signaling rescues endocrine lineage formation in Sel1l βgeo/ βgeo embryos
The genetic determinants underlying vertebrate pancreatic development are not completely understood. In the present study, we report that Sel1l expression in the developing mouse pancreas coincides with differentiation of the endocrine and exocrine lineages during the second transition. Embryos homozygous for a gene trap insertion in Sel1l display impaired pancreatic epithelial growth and differentiation. Pharmacological inhibition of Notch signaling partially rescues the pancreatic phenotype of SEL1L-deficient embryos. Together, these data provide evidence that Sel1l is required for growth and differentiation of the mammalian pancreatic epithelial cells. The underlying mechanism may be that Sel1l functions as a negative regulator for the Notch signaling pathway by facilitating degradation of the Notch intracellular domain.
Donoviel et. al. previously reported that the mouse Sel1l gene is highly transcribed in the acini of the developing pancreas at E14.5 and E17.5 . We show, by immunohistological analysis of the β-galactosidase reporter in Sel1l, that Sel1l is also highly expressed in early glucagon+ and insulin+ cells (Fig. 1C and 1D, respectively) generated during the first transition period of pancreatic development [5, 51, 52]. Consistent with the Sel1l mRNA expression pattern reported by Donoviel et. al., we reveal that at E14.5 Sel1l is broadly expressed in the PDX1+ pancreatic epithelia (Fig. 1E). Interestingly, significantly lower Sel1l expression is observed in the undifferentiated pancreatic epithelial cells (Fig. 1F) that express SOX9 [10, 11]. Our findings therefore indicate that Sel1l expression is enhanced in the committed pancreatic epithelial cells or differentiated endocrine and exocrine cells.
The selective expression of Sel1l in differentiating or differentiated pancreatic epithelial cells is highly suggestive of a role for Sel1l in promoting lineage differentiation during the secondary transition. To define the role of Sel1l in pancreatic development, we characterized the pancreatic phenotype of embryos homozygous for a gene trap insertion in Sel1l. We show that wild-type and Sel1l-deficient embryos have a comparable pancreatic epithelial size at E11.5 (Fig. 2A-B and 2E), suggesting that Sel1l function is dispensable for the induction and early growth of pancreatic epithelial cells. At E13.5, however, Sel1l-deficient pancreatic epithelia are significantly smaller and display an impaired branching morphology (Fig. 2C-D and 2F). Importantly, Sel1l-deficient pancreatic epithelia at E15.5 completely lack amylase+ cells (Fig. 3F) and have significantly reduced numbers of glucagon+ and insulin+ cells (Fig. 3D and 3F, respectively). Also, by analyzing the phenotype of cultured Sel1l-deficient dorsal pancreatic epithelia, we confirmed that the pancreatic defects in Sel1l-deficient embryos are not due to the effect of global growth retardation of the Sel1l-deficient embryos (Fig. 4A-D). Together, these data strongly suggest that Sel1l plays an important role in mouse pancreatic organogenesis by facilitating differentiation of the endocrine and exocrine lineages of the pancreas.
The C. elegans ortholog of the mammalian Sel1l gene, Sel-1, was originally identified by genetic screening as a negative regulator for lin-12/Notch signaling [44, 53]. Biochemical studies have shown that Sel-1 regulates lin-12/Notch receptor turnover [45, 46]. Whether or not Sel1l has similar functions in the mammalian system remains unclear . In this study, we provide two lines of evidence that suggest Sel1l also functions as a negative regulator for Notch signaling, at least in the developing mouse pancreas. First, the observed pancreatic phenotype in Sel1l mutant embryos show remarkable similarity to the pancreatic phenotype of transgenic vertebrate embryos over-expressing the Notch intracellular domain, the constitutively active form of Notch [26, 28, 50]. Second, we show that treatment of cultured Sel1l-deficient pancreatic epithelium with DAPT, a potent Notch signaling inhibitor, partially rescues the growth and differentiation defects of Sel1l-deficient pancreatic epithelium (Fig. 6D and 6F).
How does SEL1L negatively control Notch signaling in the developing mammalian pancreas is the focus of our current investigation. Genetic and biochemical evidences from other organisms such as Drsophila and C. elegans suggest that Notch signaling is regulated at multiple levels and through multiple mechanisms, including stochastical gene expression , selective ligand-receptor interactions , intracellular trafficking , and stability of NICD, the active form of Notch receptors . Given the previous finding that mammalian NICD are ubiquitinated and degraded through both the proteasomal and lysosomal systems [55, 56], it is conceivable that Sel1l may be directly or indirectly involved in control of NICD degradation. In this regard, it is noteworthy to mention that recent biochemical data from our laboratory indicate that NICD has significantly higher protein stability in Sel1l-deficient MEF cells (data not shown). Further proof of this hypothesis will require a detailed biochemical analysis of SEL1L and Notch interactions.
Biochemical evidences from other laboratories have also underscored the importance of Sel1l in maintaining ER homeostasis. SEL1L interacts with the E3 ubiquitin ligase HRD1 to facilitate the dislocation of unfolded or misfolded proteins from the ER lumen into the cytosol for degradation [48, 49, 57–60]. Consistent with this, we have recently shown that homozygous Sel1l mutant mice develop systemic ER stress. The impact of ER stress on pancreatic epithelial proliferation and differentiation remains undefined from the current study. However, several hypothetical roles of ER stress in pancreatic organ development and growth can be proposed. First, ER stress affects global gene expression. Upon ER stress, translation is generally down to reduce production of ER client proteins. Concomitantly, transcription of genes encoding ER chaperones and ER-associated degradation (ERAD) machinery is increased. Second, ER stress blocks or reduces protein secretion by mammalian cells. This will directly affect cell signaling and cell functions. Finally, prolonged ER stress activates the signaling pathways leading to apoptosis.
We report that during mouse pancreatic development, Sel1l is preferentially expressed in the differentiating or differentiated pancreatic epithelial cells. Disruption of Sel1l function results in impaired endocrine lineage formation and delayed exocrine lineage differentiation. Pharmacological suppression of Notch signaling in cultured pancreatic explants partially rescues the endocrine cell differentiation defect. Our data suggest that Sel1l may regulate pancreatic epithelial growth and differentiation by suppressing Notch-mediated signaling.
Sel1l gene trap mice
The chimeric founder mouse used to generate Sel1l gene trap mice was generated by microinjection of a commercially available mouse embryonic stem (ES) cell clone, CA0017, into C57/BL6 blastocysts. This ES cell clone contains a gene trap insertion in the 14th intron of the Sel1l gene. All mice or mouse embryos were genotyped by PCR analysis of tail or toe genomic DNA using the following PCR primers:
All animal experiments were performed in accordance with the Cornell Animal Care and Use Guidelines.
Histology and immunohistochemistry
Embryos or pancreatic rudiments were fixed in 4% paraformaldehyde (PFA) in PBS at 4°C for 12 hours or longer. PFA-fixed specimens were equilibrated in 30% sucrose in PBS at 4°C and embedded in O.C.T. Sections were cut at 10 μm and immunostained essentially as described [61, 62]. Briefly, tissue sections were permeabilized with 0.2% Triton X-100 in PBS for 20 min, washed 3 times in 0.1% Triton X-100 in PBS and 3 times in PBS. The permeabilized sections were pre-incubated with 5% normal donkey serum and 1% BSA in PBS at room temperature for at least 1 hour, followed by incubation in the same solution with primary antibodies at 4°C overnight. The antibody-bound sections were then washed three times in 0.1% Triton X-100 in PBS, 3 times in PBS and then incubated with secondary antibodies for 1-3 hrs at room temperature. Primary antibodies were diluted in 1% BSA in PBS as follows: rabbit anti-b-Galactosidase (Immunology Consultants Laboratory), 1:500; guinea pig anti-Pdx-1 (Abcam), 1:1000; goat anti-Pdx1 (Abcam), 1:1000; guinea pig anti-insulin (Linco), 1:1000; rabbit anti-glucagon (Covance), 1:500; goat anti-glucagon (AbD Serotec), 1:200; rabbit anti-Sox9 (gift from Dr. Michael Wegner), 1:1000; rabbit anti-Ptf1a (gift from Dr. Helena Edlund), 1:1000); and rabbit anti-amylase (Sigma), 1:500. Secondary antibodies were diluted in 1% BSA in PBS as follows: donkey anti-rabbit IgG conjugated to Cy3 (Jackson Immuno Research), 1:1000; donkey anti-guinea pig IgG conjugated to Cy2 (Jackson Immuno Research), 1:500. Fluorescence images were acquired using an Axiovert 40 microscope (Zeiss) equipped with an AxioCam camera.
Pancreatic morphometry and cell counting
Quantitative morphometry of the developing pancreas and cell counting were performed essentially as described . Briefly, pancreata of age-matched wild-type and Sel1l βgeo/ βgeo embryos were sectioned through and every fifth section was immunostained with anti-PDX1 or co-immunostained with anti-PDX1 and anti-Glucagon. Quantification of pancreatic epithelium area (PDX1+ area) was performed using AxioVision Imaging analysis software (version 4.6.3). The data were presented as averages ± SEM (μm2) of three independent pancreata. Statistical analysis was performed using the Student's two-sample t test and significance is regarded as p ≤ 0.05.
Pancreatic organ culture and DAPT treatment
Sel1l+/βgeomice were intercrossed to generate embryos of defined genotypes: wild-type (Sel1l+/+), heterozygous (Sel1l+/βgeo) and homozygous (Sel1l βgeo/ βgeo ). The day of the vaginal plug was taken as embryonic (E) day 0.5. Pancreatic bud dissection and culture were performed essentially as described . Briefly, E11.5 embryos were decapitated and the dorsal pancreatic rudiment together with surrounding mesenchymal tissue was removed in PBS. The dissected pancreatic buds were rinsed once in culture medium, transferred to a fibronectin-coated 8-well LabTek chamber slide with the epithelial side touching the bottom of the slide and cultured for 72 hours in basal medium with Earle's salts (Gibco 21010-046), 1 × glutamine, 10% FBS and antibiotics. The cultured pancreatic rudiments were fixed individually for 30 minutes in 4% paraformaldehyde in PBS for immunohistological analysis. DAPT treatment of cultured pancreatic explants was performed essentially as described . DAPT stock solution was prepared at a concentration of 10 mM in DMSO and was aliquoted into single-usage aliquots. For Notch inhibition experiments, pancreatic buds were cultured in complete medium containing 10 μM of DAPT. Control pancreatic buds were cultured in complete medium containing 0.1% DMSO. The DMSO or DAPT-treated pancreatic buds were briefly fixed and analyzed by immunostaining.
We thank Dr. Patrick Biggs (Sanger Institute, UK) for generously providing the CA0017 mouse ES cell line; Drs. Raymond MacDonald (The University of Texas Southwestern Medical Center), Chyio Shiota and George Gittes (The University of Pittsburgh School of Medicine) for useful information about pancreatic explants culture; Drs. Yves Boisclair and Bruce Currie (Cornell University) for stimulating discussions and critical comments during preparation of the manuscript. The financial support for this research project was provided by the College of Agricultural and Life science, Cornell University to QL.
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