Sonic hedgehog Is Required Early in Pancreatic Islet Development

Diiorio, Philip J.; Moss, Jane; Sbrogna, Jennifer L.; Karlstrom, Rolf O.; Moss, Larry G.

doi:10.1006/dbio.2002.0573

Cited by 107 publications

(91 citation statements)

References 53 publications

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“…Zebrafish with loss-of-function mutations in Shh (syu) or Smoothened (smo), as well as zebrafish embryos treated with cyclopamine (a hedgehog inhibitor), exhibit disrupted Pdx1 expression and endocrine pancreas does not form (Roy et al, 2001;diIorio et al, 2002). It was proposed that Shh from the notochord induces pancreas development in zebrafish through mechanisms that appear to mimic the late role of Shh in regulating amniote endocrine cell function.…”

Section: Dorsal Pancreas Induction: Signaling From Notochord and Vascmentioning

confidence: 99%

Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

529

594

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Pancreas oganogenesis comprises a coordinated and highly complex interplay of signaling events and transcriptional networks that guide a step-wise process of organ development from early bud specification all the way to the final mature organ state. Extensive research on pancreas development over the last few years, largely driven by a translational potential for pancreatic diseases (diabetes, pancreatic cancer, and so on), is markedly advancing our knowledge of these processes. It is a tenable goal that we will one day have a clear, complete picture of the transcriptional and signaling codes that control the entire organogenetic process, allowing us to apply this knowledge in a therapeutic context, by generating replacement cells in vitro, or perhaps one day to the whole organ in vivo. This review summarizes findings in the past 5 years that we feel are amongst the most significant in contributing to the deeper understanding of pancreas development. Rather than try to cover all aspects comprehensively, we have chosen to highlight interesting new concepts, and to discuss provocatively some of the more controversial findings or proposals. At the end of the review, we include a perspective section on how the whole pancreas differentiation process might be able to be unwound in a regulated fashion, or redirected, and suggest linkages to the possible reprogramming of other pancreatic cell-types in vivo, and to the optimization of the forward-directed-differentiation of human embryonic stem cells (hESC), or induced pluripotential cells (iPSC), towards mature b-cells. Developmental Dynamics 240:530-565,

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Section: Dorsal Pancreas Induction: Signaling From Notochord and Vascmentioning

confidence: 99%

Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

529

594

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“…[108][109][110][111] Supporting the utility of this animal model is the finding that mutations affecting zebrafish pancreas development are readily identifiable. [112][113][114][115][116] Furthermore, anti-sense experiments have demonstrated that conserved molecular pathways regulate zebrafish and mammalian pancreas development. 114,[117][118] Conceivably, genes regulating the expression of STK11/LKB1 as well as interacting proteins and downstream effector molecules can be identified in zebrafish that will complement the studies from mammalian model organisms.…”

Section: Developmental Roles Of Stk11/lkb1mentioning

confidence: 99%

Clinicopathologic and Molecular Features of Pancreatic Adenocarcinoma Associated with Peutz-Jeghers Syndrome

Yee

Furth

Pack

2003

Cancer Biology & Therapy

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Pancreatic cancer is increasingly prevalent and almost uniformly fatal. Studies of the molecular genetics of sporadic and hereditary cases of pancreatic cancer as well as the molecular biology of pancreatic development may advance our understanding of the mechanism underlying pathogenesis of this malignancy. Based on a case of pancreatic adenocarcinoma in a patient with Peutz-Jeghers syndrome (PJS), the clinicopathologic features and molecular genetics of pancreatic tumors associated with this hereditary cancer syndrome are reviewed. Particular emphasis is placed on the developmental roles and biochemical functions of STK11/LKB1, the gene mainly responsible for PJS. Modeling pancreatic cancer in animal models such as the mouse and zebrafish will further our understanding of the pathogenesis of this important disease, and the studies derived from these model organisms can be potentially applied for developing novel preventive and therapeutic strategies.

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“…49 Interestingly, hedgehog signaling also plays an important role in the formation of the pancreas. [50][51][52][53] Ectopic expression of sonic hedgehog (Shh) inhibits pancreas formation while loss of indian hedgehog (Ihh) results in increased pancreas size with abnormal branching of ducts. [50][51][52] In addition to developmental roles, hedgehog signaling is required for normal pancreatic physiology.…”

mentioning

confidence: 99%

“…Ihh, patched, and smoothened are expressed in the islets of the adult pancreas, and recent publications suggest that bcells are a target for hedgehog signaling. [53][54][55] Cyclopamine, a hedgehog signaling inhibitor, decreases both insulin secretion as well as insulin content of b-cells in cell culture. [55][56][57] Furthermore, male mice heterozygous for patched mutations have impaired glucose homeostasis.…”

mentioning

confidence: 99%

Disruption of IFT results in both exocrine and endocrine abnormalities in the pancreas of Tg737 mutant mice

Zhang

Davenport

Croyle

et al. 2005

Laboratory Investigation

100

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While relatively ignored for years as vestigial, cilia have recently become the focus of intense interest as organelles that result in severe pathologies when disrupted. Here, we further establish a connection between cilia dysfunction and disease by showing that loss of polaris (Tg737), an intraflagellar transport (IFT) protein required for ciliogenesis, causes abnormalities in the exocrine and endocrine pancreas of the Tg737 orpk mouse. Pathology is evident late in gestation as dilatations of the pancreatic ducts that continue to expand postnatally. Shortly after birth, the acini become disorganized, undergo apoptosis, and are largely ablated in late stage pathology. In addition, serum amylase levels are elevated and carboxypeptidase is abnormally activated within the pancreas. Ultrastructural analysis reveals that the acini undergo extensive vacuolization and have numerous 'halo-granules' similar to that seen in induced models of pancreatitis resulting from duct obstruction. Intriguingly, although the acini are severely affected in Tg737 orpk mutants, cilia and Tg737 expression are restricted to the ducts and islets and are not detected on acinar cells. Analysis of the endocrine pancreas in Tg737 orpk mutants revealed normal differentiation and distribution of cell types in the islets. However, after fasting, mutant blood glucose levels are significantly lower than controls and when challenged in glucose tolerance tests, Tg737 orpk mutants exhibited defects in glucose uptake. These findings are interesting in light of the recently proposed role for polaris, the protein encoded by the Tg737 gene, in the hedgehog pathway and hedgehog signaling in insulin production and glucose homeostasis.

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Sonic hedgehog Is Required Early in Pancreatic Islet Development

Cited by 107 publications

References 53 publications

Pancreas organogenesis: From bud to plexus to gland

Pancreas organogenesis: From bud to plexus to gland

Clinicopathologic and Molecular Features of Pancreatic Adenocarcinoma Associated with Peutz-Jeghers Syndrome

Disruption of IFT results in both exocrine and endocrine abnormalities in the pancreas of Tg737 mutant mice

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