Perfluorodecanoic acid (PFDA) increases oxidative stress through inhibition of mitochondrial β-oxidation.

PER: and polyfluoroalkyl substances (PFAS) are a large group of synthetic organic chemicals that are ubiquitous environmental pollutants. Among PFAS, perfluorodecanoic acid (PFDA) is one of the most toxic compounds, but the molecular basis behind its toxicity is not fully understood. In an interspecies comparison with placental cells (HTR-8/SVneo) and zebrafish embryos, we demonstrate that PFDA induces mitochondrial dysfunction and impairs fatty acid β-oxidation.

Laboratory Course Using Zebrafish to Uncover Changing Roles of Wnt Signaling in Early Vertebrate Development.

Coordinated signaling pathway activity directs early patterning to set up the vertebrate body plan. Perturbations in the timing or location of signal molecule expression impacts embryo morphology and organ formation. In this study, we present a laboratory course to use zebrafish for studying the role of Wnt signaling in specifying the early embryonic axes.

Mitochondrial network expansion and dynamic redistribution during islet morphogenesis in zebrafish larvae.

Mitochondria, organelles critical for energy production, modify their shape and location in response to developmental state and metabolic demands. Mitochondria are altered in diabetes, but the mechanistic basis is poorly defined, due to difficulties in assessing mitochondria within an intact organism. Here, we use in vivo imaging in transparent zebrafish larvae to demonstrate filamentous, interconnected mitochondrial networks within islet cells.

Differential Responses of Neural Retina Progenitor Populations to Chronic Hyperglycemia.

Diabetic retinopathy is a frequent complication of longstanding diabetes, which comprises a complex interplay of microvascular abnormalities and neurodegeneration. Zebrafish harboring a homozygous mutation in the pancreatic transcription factor display a diabetic phenotype with survival into adulthood, and are therefore uniquely suitable among zebrafish models for studying pathologies associated with persistent diabetic conditions. We have previously shown that, starting at three months of age, mutants exhibit not only vascular but also neuro-retinal pathologies manifesting as photoreceptor dysfunction and loss, similar to human diabetic retinopathy.

Inducible Mosaic Cell Labeling Provides Insights Into Pancreatic Islet Morphogenesis.

Pancreatic islets, discrete microorgans embedded within the exocrine pancreas, contain beta cells which are critical for glucose homeostasis. Loss or dysfunction of beta cells leads to diabetes, a disease with expanding global prevalence, and for which regenerative therapies are actively being pursued. Recent efforts have focused on producing mature beta cells , but it is increasingly recognized that achieving a faithful three-dimensional islet structure is crucial for generating fully functional beta cells.

Photoreceptor Degeneration Accompanies Vascular Changes in a Zebrafish Model of Diabetic Retinopathy.

Purpose: Diabetic retinopathy (DR) is a leading cause of vision impairment and blindness worldwide in the working-age population, and the incidence is rising. Until now it has been difficult to define initiating events and disease progression at the molecular level, as available diabetic rodent models do not present the full spectrum of neural and vascular pathologies. Zebrafish harboring a homozygous mutation in the pancreatic transcription factor pdx1 were previously shown to display a diabetic phenotype from larval stages through adulthood.

FoxH1 represses miR-430 during early embryonic development of zebrafish via non-canonical regulation.

Background: FoxH1 is a forkhead transcription factor with conserved key functions in vertebrate mesoderm induction and left-right patterning downstream of the TGF-beta/Nodal signaling pathway. Binding of the forkhead domain (FHD) of FoxH1 to a highly conserved proximal sequence motif was shown to regulate target gene expression.

Results: We identify the conserved microRNA-430 family (miR-430) as a novel target of FoxH1.

imaging of emerging endocrine cells reveals a requirement for PI3K-regulated motility in pancreatic islet morphogenesis.

The three-dimensional architecture of the pancreatic islet is integral to beta cell function, but the process of islet formation remains poorly understood due to the difficulties of imaging internal organs with cellular resolution. Within transparent zebrafish larvae, the developing pancreas is relatively superficial and thus amenable to live imaging approaches. We performed time-lapse and longitudinal imaging studies to follow islet development, visualizing both naturally occurring islet cells and cells arising with an accelerated timecourse following an induction approach.

Artemisinins Target GABA Receptor Signaling and Impair α Cell Identity.

Type 1 diabetes is characterized by the destruction of pancreatic β cells, and generating new insulin-producing cells from other cell types is a major aim of regenerative medicine. One promising approach is transdifferentiation of developmentally related pancreatic cell types, including glucagon-producing α cells. In a genetic model, loss of the master regulatory transcription factor Arx is sufficient to induce the conversion of α cells to functional β-like cells.

Diabetic pdx1-mutant zebrafish show conserved responses to nutrient overload and anti-glycemic treatment.

Diabetes mellitus is characterized by disrupted glucose homeostasis due to loss or dysfunction of insulin-producing beta cells. In this work, we characterize pancreatic islet development and function in zebrafish mutant for pdx1, a gene which in humans is linked to genetic forms of diabetes and is associated with increased susceptibility to Type 2 diabetes. Pdx1 mutant zebrafish have the key diabetic features of reduced beta cells, decreased insulin and elevated glucose.

Requirement for Pdx1 in specification of latent endocrine progenitors in zebrafish.

Background: Insulin-producing beta cells emerge during pancreas development in two sequential waves. Recently described later-forming beta cells in zebrafish show high similarity to second wave mammalian beta cells in developmental capacity. Loss-of-function studies in mouse and zebrafish demonstrated that the homeobox transcription factors Pdx1 and Hb9 are both critical for pancreas and beta cell development and discrete stage-specific requirements for these genes have been uncovered.

Molecular regulation of pancreas development in zebrafish.

The pancreas is a vertebrate-specific organ of endodermal origin which is responsible for production of digestive enzymes and hormones involved in regulating glucose homeostasis, in particular insulin, deficiency of which results in diabetes. Basic research on the genetic and molecular pathways regulating pancreas formation and function has gained major importance for the development of regenerative medical approaches aimed at improving diabetes treatment. Among the different model organisms that are currently used to elucidate the basic pathways of pancreas development and regeneration, the zebrafish is distinguished by its unique opportunities to combine genetic and pharmacological approaches with sophisticated live-imaging methodology, and by its ability to regenerate the pancreas within a short time.