The transition of pancreatic progenitor cells to mature beta cells is regulated by the interaction of several transcription factors, including members of the sex-determining region on Y box (SOX) family of transcription factors. The SOX proteins are widely involved in cell fate determination and the development of several tissues, including bone, heart, gonads, lymphocytes, and glial cells as well as the pancreas. In this review, we will present recent findings that illustrate the critical role of SOX transcription factors in maintaining pancreatic progenitor cell pools and in controlling pancreatic islet morphogenesis and islet function. Interrelationships between the SOX family and other pancreatic transcription factors specific to endocrine lineages will also be discussed in light of islet cell-based therapies for the treatment of diabetes.
Get full access to this article
View all access options for this article.
References
1.
SanderM and GermanMS. (1997). The beta cells transcription factors and development of the pancreas. J Mol Med, 75:327–340.
2.
KimSK and HebrokM. (2001). Intercellular signals regulating pancreas development and function. Genes Dev, 15:111–127.
3.
ChakrabartiSK and MirmiraRG. (2003). Transcription factors direct the development and function of pancreatic beta cells. Trends Endocrinol Metab, 14:78–84.
4.
LioubinskiO, MullerM, WegnerM and SanderM. (2003). Expression of sox transcription factors in the developing mouse pancreas. Dev Dyn, 227:402–408.
5.
LyttleBM, LiJ, KrishnamurthyM, FellowsF, WheelerMB, GoodyerCG and WangR. (2008). Transcription factor expression in the developing human fetal endocrine pancreas. 51,(7):1169–1180.
6.
JensenJ. (2004). Gene regulatory factors in pancreatic development. Dev Dyn, 229:176–200.
7.
HabenerJF, KempDM and ThomasMK. (2005). Minireview: transcriptional regulation in pancreatic development. Endocrinology, 146:1025–1034.
8.
SlackJM. (1995). Developmental biology of the pancreas. Development, 121:1569–1580.
9.
TeitelmanG, AlpertS, PolakJM, MartinezA and HanahanD. (1993). Precursor cells of mouse endocrine pancreas coexpress insulin, glucagon and the neuronal proteins tyrosine hydroxylase and neuropeptide Y, but not pancreatic polypeptide. Development, 118:1031–1039.
10.
PiperK, BrickwoodS, TurnpennyLW, CameronIT, BallSG, WilsonDI and HanleyNA. (2004). Beta cell differentiation during early human pancreas development. J Endocrinol, 181:11–23.
11.
HuangHP and TsaiMJ. (2000). Transcription factors involved in pancreatic islet development. J Biomed Sci, 7:27–34.
GuG, DubauskaiteJ and MeltonDA. (2002). Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development, 129:2447–2457.
14.
OffieldMF, JettonTL, LaboskyPA, RayM, SteinRW, MagnusonMA, HoganBL and WrightCV. (1996). PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development, 122:983–995.
15.
GradwohlG, DierichA, LeMeurM and GuillemotF. (2000). Neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas. Proc Natl Acad Sci USA, 97:1607–1611.
16.
WilsonME, YangKY, KalousovaA, LauJ, KosakaY, LynnFC, WangJ, MrejenC, EpiskopouV, CleversHC and GermanMS. (2005). The HMG box transcription factor Sox4 contributes to the development of the endocrine pancreas. Diabetes, 54:3402–3409.
17.
SeymourPA, FreudeKK, TranMN, MayesEE, JensenJ, KistR, SchererG and SanderM. (2007). SOX9 is required for maintenance of the pancreatic progenitor cell pool. Proc Natl Acad Sci USA, 104:1865–1870.
18.
LynnFC, SmithSB, WilsonME, YangKY, NekrepN and GermanMS. (2007). Sox9 coordinates a transcriptional network in pancreatic progenitor cells. Proc Natl Acad Sci USA, 104:10500–10505.
19.
GubbayJ, CollignonJ, KoopmanP, CapelB, EconomouA, MunsterbergA, VivianN, GoodfellowP and Lovell-BadgeR. (1990). A gene mapping to the sex-determining region of the mouse Y chromosome is a member of a novel family of embryonically expressed genes. Nature, 346:245–250.
20.
SchepersGE, TeasdaleRD and KoopmanP. (2002). Twenty pairs of sox: Extent, homology, and nomenclature of the mouse and human sox transcription factor gene families. Dev Cell, 3:167–170.
21.
WilsonM and KoopmanP. (2002). Matching SOX: Partner proteins and co-factors of the SOX family of transcriptional regulators. Curr Opin Genet Dev, 12:441–446.
22.
LaudetV, StehelinD and CleversH. (1993). Ancestry and diversity of the HMG box superfamily. Nucleic Acids Res, 21:2493–501.
23.
SoullierS, JayP, PoulatF, VanackerJM, BertaP and LaudetV. (1999). Diversification pattern of the HMG and SOX family members during evolution. J Mol Evol, 48:517–527.
24.
BowlesJ, SchepersG and KoopmanP. (2000). Phylogeny of the SOX family of developmental transcription factors based on sequence and structural indicators. Dev Biol, 227:239–255.
25.
LefebvreV, DumitriuB, Penzo-MéndezA, HanY and PallaviB. (2007). Control of cell fate and differentiation by Sry-related high-mobility-group box (Sox) transcription factors. Int J Biochem Cell Biol, 39:2195–2214.
26.
WegnerM. (1999). From head to toes: the multiple facets of sox proteins. Nucleic Acids Res, 27:1409–1420.
27.
WeissMA. (2001). Floppy SOX: mutual induced fit in hmg (high-mobility group) box-DNA recognition. Mol Endocrin, 15:353–362.
28.
PevnyLH and Lovell-BadgeR. (1997). Sox genes find their feet. Curr Opin Genet Dev, 7:338–344.
29.
KamachiY, UchikawaM and KondohH. (2000). Pairing SOX off: with partners in the regulation of embryonic development. Trends Genet, 16:182–187.
30.
IguchiH, IkedaY, OkamuraM, TanakaT, UrashimaY, OhguchiH, TakayasuS, KojimaN, IwasakiS, OhashiR, JiangS, HasegawaG, IokaRX, MagooriK, SumiK, MaejimaT, UchidaA, NaitoM, OsbourneTF, YanagisawaM, YamamotoTT, KodamaT and SakaiJ. (2005). SOX6 attenuates glucose-stimulated insulin secretion by repressing PDX1 transcriptional activity and is down-regulated in hyperinsulinemic obese mice. J Biol Chem, 280:37669–37680.
31.
PiperK, BallSG, KeelingJW, MansoorS, WilsonDI and HanleyNA. (2002). Novel SOX9 expression during human pancreas development correlates to abnormalities in campomelic dysplasia. Mech Dev, 116:223–226.
32.
WangY, RistevskiS and HarleyVR. (2006). SOX13 exhibits a distinct spatial and temporal expression pattern during chondrogenesis, neurogenesis, and limb development. J Histochem Cytochem, 54:1327–1333.
33.
ZhaoM, AmielSA, ChristieMR, MuiesanP, SrinivasanP, LittlejohnW, RelaM, ArnoM, HeatonN and HuangGC. (2007). Evidence for the presence of stem cell-like progenitor cells in human adult pancreas. J Endocrinol, 195:407–414.
34.
HoserM, PotznerMR, KochJM, MRBösl, WegnerM and SockE. (2008). Sox12 deletion in the mouse reveals nonreciprocal redundancy with the related Sox4 and Sox11 transcription factors. Mol Cell Biol, 28:4675–4687.
35.
SchilhamMW, OosterwegelMA, MoererP, YaJ, de BoerPA, van de WeteringM, VerbeekS, LamersWH, KruibeekAM, CumanoA and CleversH. (1996). Defects in cardiac outflow tract formation and pro-B-lymphocyte expansion in mice lacking Sox-4. Nature, 380:711–714.
36.
SockE, RettigSD, EnderichJ, MRBösl, TammER and WegnerM. (2004). Gene targeting reveals a widespread role for the high-mobility-group transcription factor Sox11 in tissue remodeling. Mol Cell Biol, 24:6635–6644.
37.
GoldsworthyM, HugillA, FreemanH, HornerE, ShimomuraK, BoganiD, PielesG, MijatV, ArkellR, BhattacharyaS, AshcroftFM and CoxRD. (2008). Role of the transcription factor sox4 in insulin secretion and impaired glucose tolerance. Diabetes, 57:2234–2244.
38.
KasimiotisH, MyersMA, ArgentaroA, MertinS, FidaS, FerraroT, OlssonJ, RowleyMJ and HarleyVR. (2000). Sex-determining region Y-related protein SOX13 is a diabetes autoantigen expressed in pancreatic islets. Diabetes, 49:555–561.
39.
ArgentaroA, WapelhorstB, ConcannonP and HarleyVR. (2001). Linkage studies of SOX13, the ICA12 autoantigen gene, in families with type 1 diabetes. Mol Genet Metab, 72:356–359.
40.
LampasonaV, ScirpoliM, BosiE and Bonifacio EE. (2001). ICA12 (SOX13) autoantibodies are unlikely to be a useful marker for pre-clinical Type I diabetes. Diabetologia, 44:267.
41.
IguchiH, UrashimaY, InagakiY, IkedaY, OkamuraM, TanakaT, UchidaA, YamamotoTT, KodamaT and SakaiJ. (2007). SOX6 suppresses cyclin D1 promoter activity by interacting with beta-catenin and histone deacetylase 1, and its down-regulation induces pancreatic beta-cell proliferation. J Biol Chem, 282:19052–19061.
42.
McDonaldE, LiJ, FellowsF, GoodyearCG and WangR. (2008). Role of SOX9 in endocrine cell differentiation in the human fetal pancreas. Can. J Diabetes Care, 32:4.
43.
LeeYH and Saint-JeannetJP. (2003). Sox9, a novel pancreatic marker in Xenopus. Int J Dev Biol, 47:459–462.
44.
SeymourPA, FreudeKK, DuboisCL, ShihHP, PatelNA and SanderM. (2008). A dosage-dependent requirement for Sox9 in pancreatic endocrine cell formation. Dev Biol, 323:19–30.
45.
Kanai-AzumaM, KanaiY, GadJM, TajimaY, TayaC, KurohmaruM, SanaiY, YonekawaH, YazakiK, TamPP and HayashiY. (2002). Depletion of definitive gut endoderm in Sox17-null mutant mice. Development, 129:2367–2379.
46.
SpenceJR, LangeAW, LinSC, KaestnerKH, LowyAM, KimI, WhitsettJA and WellsJM. (2009). Sox17 regulates organ lineage segregation of ventral foregut progenitor cells. Dev Cell, 17:62–74.
