Animal Models of Pancreas Development, Developmental Disorders, and Disease

Lorberbaum, David S.; Docherty, Fiona M.; Sussel, Lori

doi:10.1007/978-981-15-2389-2_3

Cited by 12 publications

(13 citation statements)

References 117 publications

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“…Constant excess nutrition promotes hyperglycemia, obesity, and type 2 diabetes 1 , 2 . Transcription factor networks orchestrated by Pdx1, Ptf1α, Sox9, Hnf1α, Gata4/6, Ngn3 are indispensable for morphogenesis and homeostasis of the pancreas and loss of any of these result in a moribund phenotype caused by hypoplasia of islets 1 , 5 , 6 , 12 , 49 . Our analyses demonstrated that pancreas organogenesis and function is also dependent on Zeb1, a transcription factor mainly confined to non-epithelial cells and a potent inducer of EMT.…”

Section: Discussionmentioning

confidence: 99%

“…Proper pancreas organ function and homeostasis is highly challenged by the life style and diets of modern societies, leading to continuously raising disorders like type 2 diabetes, pancreatitis, and pancreatic cancer 1 – 4 . The pancreas is organized in an exocrine compartment, producing and releasing digestive enzymes into the intestine, and an endocrine compartment, i.e., the islets of Langerhans 2 .…”

Section: Introductionmentioning

confidence: 99%

“…During development the pancreas in mice is specified at E9.0 by budding from the ventral foregut endoderm into dorsal and ventral parts that eventually fuse at E12.5 1 , 5 , 6 . Pdx1 expression is initiated in multiprogenitor cells that are specified by local repression of Shh, involving activin, retinoic acid, FGF, and BMP signals 1 , 5 , 6 . Pdx1, Ptf1α, and Sox9 are crucial for pancreas organogenesis and loss of any of these factors results in agenesis or hypoplasia 7 – 10 .…”

Section: Introductionmentioning

confidence: 99%

“…Ptf1α and Nkx6.1/Nkx6.2 specify tip and trunk cells, respectively, by repressing each other’s expression, orchestrated by the Notch pathway 5 , 12 , 14 – 16 . Secondary transition is initiated at E12.5 and lasts until E16.5, involving continued branching morphogenesis and specification of tip cells into acini by E15.5 and of endocrine progenitors by delamination of individual Ngn3+ cells from the monolayer epithelium of the trunk to form islets 1 , 11 , 16 – 19 . During the second transition Ptf1α, Pdx1 and Sox9 become restricted to acini, islets and ducts, respectively 6 .…”

Section: Introductionmentioning

confidence: 99%

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Pancreas morphogenesis and homeostasis depends on tightly regulated Zeb1 levels in epithelial cells

et al. 2021

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The pancreas is comprised of exocrine and endocrine compartments releasing digestive enzymes into the duodenum and regulating blood glucose levels by insulin and glucagon release. Tissue homeostasis is depending on transcription factor networks, involving Ptf1α, Ngn3, Nkx6.1, and Sox9, which are already activated during organogenesis. However, proper organ function is challenged by diets of high sugar and fat content, increasing the risk of type 2 diabetes and other disorders. A detailed understanding of processes that are important for homeostasis and are impaired during type 2 diabetes is lacking. Here, we show that Zeb1—a transcription factor known for its pivotal role in epithelial-mesenchymal transition, cell plasticity, and metastasis in cancer—is expressed at low levels in epithelial cells of the pancreas and is crucial for organogenesis and pancreas function. Loss of Zeb1 in these cells result in an increase of islet mass, impaired glucose tolerance, and sensitizes to develop liver and pancreas steatosis during diabetes and obesity. Interestingly, moderate overexpression of Zeb1 results in severe pancreas agenesis and lethality after birth, due to islet insufficiency and lack of acinar structures. We show that Zeb1 induction interferes with proper differentiation, cell survival, and proliferation during pancreas formation, due to deregulated expression of endocrine-specific transcription factors. In summary, our analysis suggests a novel role of Zeb1 for homeostasis in epithelial cells that is indispensable for pancreas morphogenesis and proper organ function involving a tight regulation of Zeb1 expression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pancreas morphogenesis and homeostasis depends on tightly regulated Zeb1 levels in epithelial cells

et al. 2021

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“…Although there are limitations of generalizing from an animal model to the condition of humans, animals can be useful to get information from a homogeneous group at the same stage of the disease, and free from other puzzling factors (Nevzorova et al, 2020). Life conditions (embryology, anatomy, and physiology) between humans and other mammals might be relatively analogous, indicating the animals as potential models for experimentation (Lorberbaum et al, 2020). An additional advantage of animal models, including nutritional research, is comparing appropriate controls, separating the effect of food intake from other metabolic effects by pair feeding, and the precise manipulation of the diet (Vianna et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Nutritional Research and Fetal Programming: Parental Nutrition Influences the Structure and Function of the Organs

2021

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The role of noncoding RNAs in pancreatic birth defects

Yang

Parchem

2023

Birth Defects Research

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Congenital defects in the pancreas can cause severe health issues such as pancreatic cancer and diabetes which require lifelong treatment. Regenerating healthy pancreatic cells to replace malfunctioning cells has been considered a promising cure for pancreatic diseases including birth defects. However, such therapies are currently unavailable in the clinic. The developmental gene regulatory network underlying pancreatic development must be reactivated for in vivo regeneration and recapitulated in vitro for cell replacement therapy. Thus, understanding the mechanisms driving pancreatic development will pave the way for regenerative therapies. Pancreatic progenitor cells are the precursors of all pancreatic cells which use epigenetic changes to control gene expression during differentiation to generate all of the distinct pancreatic cell types. Epigenetic changes involving DNA methylation and histone modifications can be controlled by noncoding RNAs (ncRNAs). Indeed, increasing evidence suggests that ncRNAs are indispensable for proper organogenesis. Here, we summarize recent insight into the role of ncRNAs in the epigenetic regulation of pancreatic development. We further discuss how disruptions in ncRNA biogenesis and expression lead to developmental defects and diseases. This review summarizes in vivo data from animal models and in vitro studies using stem cell differentiation as a model for pancreatic development.

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Animal Models of Pancreas Development, Developmental Disorders, and Disease

Cited by 12 publications

References 117 publications

Pancreas morphogenesis and homeostasis depends on tightly regulated Zeb1 levels in epithelial cells

Pancreas morphogenesis and homeostasis depends on tightly regulated Zeb1 levels in epithelial cells

Nutritional Research and Fetal Programming: Parental Nutrition Influences the Structure and Function of the Organs

The role of noncoding RNAs in pancreatic birth defects

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