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Associate Member, St. Jude Faculty
Beatriz Sosa-Pineda, PhD
MS 331, Room D-3055E
St. Jude Children's Research Hospital
262 Danny Thomas Place
Memphis, TN 38105-3678
Molecular and cellular mechanisms of pancreas and liver organogenesis
The formation of distinct organs of vertebrates requires intricate molecular interactions involving transcription factors, extracellular matrix components, and signaling molecules working with their cognate receptors. Numerous studies have shown that the reactivation of certain developmental pathways is necessary for repair or regeneration of tissues and for the progression of certain pathologies (e.g., cancer). Thus, elucidating the molecular and cellular mechanisms that govern organogenesis is necessary for the understanding of not only embryology, but also the origin of certain diseases and the mechanisms involved in organ regeneration.
In mammals, the pancreas and the liver accomplish specific functions that are critical for the assimilation of nutrients, for energy supply, and for maintaining homeostasis. Our long-term research goals aim toward understanding how the liver and the pancreas form in mammalian embryos. To accomplish our objectives, we utilize various mouse models produced in our laboratory and by other researchers, and we culture pancreas and liver explants of embryos to analyze their development in vitro under specific conditions.
Studies on pancreas organogenesis
Our previous studies showed that the functions of Pax4 and Prox1, two homeodomain-containing transcription factors, are necessary for proper pancreas organogenesis in mice. Specifically, we found that Pax4 is a critical regulator of the specification of insulin-producing b-cell precursors in the pancreas, as its loss of function aberrantly converts those precursors into ghrelin-producing cells (Sosa-Pineda et al., 1997; Wang et al., 2004; Prado et al., 2005; Wang et al., 2008). We also showed that the function of Prox1 is necessary for proper morphogenesis, growth, and cell differentiation in the early pancreatic tissues of embryos (Wang et al., 2005). More recently, we showed that the conditional deletion of Prox1 in pancreatic progenitors affects multiple aspects of late pancreas organogenesis, promotes extensive apoptosis of exocrine cells at postnatal stages, and results in a low level of inflammation that severely compromises homeostasis of the mutant organ in adulthood (Kilic et al., submitted for publication). Collectively, the results of our investigations highlight the critical requirement of Prox1 function for the formation of a fully functional pancreas.
Our current studies aim to dissect the molecular pathways controlled by Prox1 in progenitors and mature cells of the pancreas, including the identification of possible Prox1 target genes and Prox1-interacting proteins in this tissue. We also are using gain-of-function and loss-of-function approaches to investigate the degree to which Prox1 controls some aspects of b-cell homeostasis. Moreover, by using in vivo approaches, we are also investigating the extent to which the loss of Prox1 function increases susceptibility to pancreatitis or contributes to the formation of pancreatic ductal carcinomas in mice.
Studies on liver organogenesis
The basic structure of the liver starts to be established during embryogenesis and is completed during postnatal stages. Uncovering the molecular and cellular mechanisms that govern mammalian liver development should be highly significant in revealing the origin of human congenital liver malformations.
Our initial characterization of the liver of Prox1-nullizygous embryos showed that the delamination of hepatoblasts is abrogated in this mutant organ (Sosa-Pineda et al., 2000). More recently, after deleting Prox1 in the liver of embryos around mid-gestation, we discovered that the differentiation of hepatoblasts is severely perturbed in the absence of Prox1 activity. Similarly, we deleted Prox1 in mature hepatocytes of mice and found various defects suggesting that Prox1 function is also required for the preservation of adult liver homeostasis. Currently, we are using various in vivo and in vitro approaches to dissect the molecular pathways controlled by Prox1 in liver tissues of embryos and adults. We expect these studies to yield valuable information on mammalian liver organogenesis and to reveal how certain molecular mechanisms contribute to the preservation of the integrity of this organ in adults.
Westmoreland JJ, Drosos Y, Kelly J, Ye J, Means AL, Washington MK and Sosa-Pineda B. Dynamic distribution of claudin proteins in pancreatic epithelia undergoing morphogenesis or neoplastic transformation. Dev. Dyn Jan 13, 2012. [Epub ahead of print]. PMCID: In Process.
Westmoreland JJ, Kilic G, Sartain C, Sirma S, Blain J, Rehg J, Harvey N, Sosa-Pineda B. Pancreas-specific deletion of Prox1 affects development and disrupts homeostasis of the exocrine pancreas. Gastroenterology December 13, 2011.[Epub ahead of print]. PMCID: In Process.
Raum JC, Hunter CS, Artner I, Henderson E, Guo M, Elghazi L, Sosa-Pineda B, Ogihara T, Mirmira RG, Sussel L, Stein R. Islet beta-cell-specific MafA transcription requires the 5'-flanking conserved region 3 control domain. Mol Cell Biol 30(17):4234-44, 2010.
Kang HS, Kim YS, ZeRuth G, Beak JY, Gerrish K, Kilic G, Sosa-Pineda B, Jensen J, Pierreux CE, Lemaigre FP, Foley J, Jetten AM. Transcription factor Glis3, a novel critical player in the regulation of pancreatic beta-cell development and insulin gene expression. Mol Cell Biol 29(24)6366-79, 2009.
Collombat P, Xu X, Ravassard P, Sosa-Pineda B, Dussaud S, Billestrup N, Madsen OD, Serup P, Heimberg H, Mansouri A. The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells. Cell 138(3):449-62, 2009.
Westmoreland JJ, Wang Q, Bouzaffour M, Baker SJ, Sosa-Pineda B. PDK1 activity controls proliferation, survival and growth of developing pancreatic cells. Developmental Biology 334(1):285-298, 2009.
Wang Q, Elghazi L, Martin S, Martins I, Srinivasan S, Geng X, Sleeman M, Collombat P, Houghton J, Sosa-Pineda B. Ghrelin is a novel target of Pax4 in endocrine progenitors of the pancreas and duodenum. Developmental Dynamics 237(1):51-61, 2008.
Kilic G, Wang J, Sosa-Pineda B. Osteopontin is a Novel Marker of Pancreatic Ductal Tissues and of Undifferentiated Pancreatic Precursors in Mice. Developmental Dynamics 235 (6): 1659-1667, 2006.
Wang J, Kilic G, Aydin M, Burke Z, Oliver G, Sosa-Pineda B. Prox1 activity controls pancreas morphogenesis and participates in the production of “secondary transition” pancreatic endocrine cells. Developmental Biology 286: 182-194, 2005.
Sosa-Pineda B. The gene Pax4 is an essential regulator of pancreatic b-cell development. Mol Cells 18(3): 289-294, 2004.
Prado CL, Pugh-Bernard AE, Elghazi L, Sosa-Pineda B, Sussel L. Ghrelin cells replace insulin-producing beta cells in two mouse models of pancreas development. PNAS 101: 4679-4684, 2004.
Wang J, Elghazi L, Parker S, Kizilocak H, Asano M, Sussel L, Sosa-Pineda B. The concerted activities of Pax4 and Nkx2.2 are essential to initiate pancreatic b-cell differentiation. Developmental Biology 266(1): 178-189, 2004.
Sosa-Pineda B, Wigle JT, Oliver G. Hepatocyte migration during liver development requires Prox1. Nat Genet 25:254-255, 2000.
Larsson L-I, St-Onge L, Hougaard DM, Sosa-Pineda B, Gruss P. Pax4 and 6 regulate gastrointestinal endocrine cell development. Mech Dev 79:153-159, 1998.
St-Onge L, Sosa-Pineda B, Chowdhury K, Mansouri A, Gruss P. Pax6 is required for differentiation of glucagon-producing a-cells in mouse pancreas. Nature 387:406-409, 1997.
Sosa-Pineda B, Chowdhury K, Torres M, Oliver G, Gruss P. The Pax4 gene is essential for differentiation of insulin-producing b cells in the mammalian pancreas. Nature 386:399-402, 1997.
Oliver G, Sosa-Pineda B, Geisendorf S, Spana EP, Doe CQ, Gruss P. Prox 1, a prospero-related homeobox gene expressed during mouse development. Mech Dev 44:3-16, 1993.
Last update: January 2012