Targeted deletion of a <i>cis</i>-regulatory region reveals differential gene dosage requirements for <i>Pdx1</i> in foregut organ differentiation and pancreas formation

Fujitani, Yoshio; Fujitani, Shuko; Boyer, Daniel F.; Gannon, Maureen; Kawaguchi, Yoshiya; Ray, Michael; Shiota, Masakazu; Stein, Roland; Magnuson, Mark A.; Wright, Christopher V.E.

doi:10.1101/gad.1360106

Cited by 145 publications

(145 citation statements)

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“…In addition, some cells were double-positive for both glucagon and insulin [23]. This is one of the first examples of the potential interconversion of endocrine subtypes, an important theme that we will discuss in more detail below.An increase in α-cell number and similarly modified islet architecture were seen in mice heterozygous for a hypomorphic Pdx1 allele [24]. Inactivation of Pdx1 in embryonic β-cells resulted in a major expansion of α-cells, which was detectable as early as E18.5 and was also seen in the adult islet.…”

mentioning

confidence: 78%

Transcriptional regulation of α‐cell differentiation

Bramswig

Kaestner

2011

Diabetes Obesity Metabolism

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The development of the endocrine pancreas and the differentiation of its five cell types, α, β, δ, ε and pancreatic polypeptide (PP) cells, are a highly complex and tightly regulated process. Proper differentiation and function of α-and β-cells are critical for blood glucose homeostasis. These processes are governed by multiple transcription factors and other signalling systems, and its dysregulation results in diabetes. The differentiation of α-cells and the maintenance of α-cell function can be influenced at several stages during development and in the maturing islet. Many transcription factors, such as neurogenin 3 (Ngn3), pancreatic duodenal homeobox 1 (Pdx1) and regulatory factor x6 (Rfx6), play a crucial role in the determination of the endocrine cell fate, while other transcription factors, such as aristaless-related homeobox (Arx) and forkhead box A2 (Foxa2), are implicated in the initial or terminal differentiation of α-cells. In vivo and in vitro studies have shown that preproglucagon transcription, and therefore the maintenance of α-cell function, is regulated by several factors, including forkhead box A1 (Foxa1), paired box 6 (Pax6), brain4 (Brn4) and islet-1 (Isl-1). Detailed information about the regulation of normal and abnormal α-cell differentiation gives insight into the pathogenesis of diabetes, identifies further targets for diabetes treatment and provides clues for the reprogramming of α-to β-cells for replacement therapy. Keywords: α-cells, diabetes, pancreatogenesis, transcriptional regulation, transdifferentiation Date submitted 1 April 2011; date of final acceptance 19 April 2011 IntroductionThe pancreas is a complex organ made up of exocrine and endocrine cells, and is crucial for nutrient digestion and blood glucose homeostasis. In the embryo, the entire pancreas originates as two buds from the foregut endoderm, and initially all pancreatic epithelial precursors express the transcriptional regulator pancreatic duodenal homeobox 1 (Pdx1) [1,2]. Acinar cells, as part of the exocrine compartment, secrete digestive enzymes into the ductal lumen system, which is connected to the duodenum. The five endocrine cell types are α, β, δ, ε and pancreatic polypeptide (PP) cells, which collectively constitute less than 2% of the mass of the pancreas, and are organized into the islets of Langerhans. The islets of Langerhans belong to the neuroendocrine system (NES), which also includes the neuronal cells of the central and peripheral nervous systems and disseminated cells in the gut mucosa [3]. During evolution, islet hormone-producing cells first appeared in the nervous system, were next seen as disseminated cells in the mucosa of the alimentary tract, and did not evolve as a separate functional unit (in the form of the islet) until the appearance of the first vertebrates.Pancreatic α-cells produce glucagon from preproglucagon via prohormone convertase 2 (PC2). Glucagon, a hormone critical for blood glucose homeostasis, stimulates hepatic gluconeogenesis and glycogenolysis. It mobilizes glucose from...

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confidence: 78%

Transcriptional regulation of α‐cell differentiation

Bramswig

Kaestner

2011

Diabetes Obesity Metabolism

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“…Low Pdx1 levels can drive largely normal development of many aspects of gut epithelium differentiation, such as gut/stomach enteroendocrine cell specification, structure of the gastro-duodenal junction, and formation of Brunner's glands . Fujitani et al (2006) also proposed the possible existence of different early progenitor populations (gutproximal and gut-distal) in the dorsal pancreas bud, which have different developmental potentials when carrying the same level of Pdx1 expression from the Pdx1 DI-II-III allele. Considering the relatively extensive deletion in the hypomorphic Pdx1 allele, these studies are considered relatively blunt.…”

Section: Pdx1mentioning

confidence: 99%

Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

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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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“…Area III appears to control the pancreas-wide expression of Pdx1 during early bud formation [41], whereas Areas I and II appear to control islet-specific expression in later development and adulthood [42][43][44]. Homozygous deletion of the entire Area I-II-III region in mice results in agenesis of the ventral pancreatic bud and hypoplasia of the dorsal bud, but without abnormalities in the stomach or duodenum [45,46]. These findings suggest that the spatial regulation of Pdx1 gene expression in the early endoderm is regulated by discrete ciselements within its promoter that are bound by trans-acting factors.…”

Section: Pdx1 and Early Pancreas Developmentmentioning

confidence: 99%

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

Babu

Deering

Mirmira

2007

Molecular Genetics and Metabolism

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Emerging evidence over the past decade indicates a central role for transcription factors in the embryonic development of pancreatic islets and the consequent maintenance of normal glucose homeostasis. Pancreatic and duodenal homeobox 1 (Pdx1) is the best studied and perhaps most important of these factors. Whereas deletion or inactivating mutations of the Pdx1 gene causes whole pancreas agenesis in both mice and humans, even haploinsufficiency of the gene or alterations in its expression in mature islet cells causes substantial impairments in glucose tolerance and the development of a late-onset form of diabetes known as maturity onset diabetes of the young. The study of Pdx1 has revealed crucial phenotypic interrelationships of the varied cell types within the pancreas, particularly as these impinge upon cellular differentiation in the embryo and neogenesis and regeneration in the adult. In this review, we describe the actions of Pdx1 in the developing and mature pancreas and attempt to unify these actions with its known roles in modulating transcriptional complex formation and chromatin structure at the molecular genetic level.

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Targeted deletion of a cis-regulatory region reveals differential gene dosage requirements for Pdx1 in foregut organ differentiation and pancreas formation

Abstract: [Keywords: Organogenesis; pancreatic ␤ cells; Pdx1; MODY; Enhancer; cis-element; foregut differentiation] Supplemental material is available at http://www.genesdev.org.

Cited by 145 publications

References 66 publications

Transcriptional regulation of α‐cell differentiation

Transcriptional regulation of α‐cell differentiation

Pancreas organogenesis: From bud to plexus to gland

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

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