| 1. |
- Arregi, Igor, et al.
(författare)
-
Retinol dehydrogenase-10 regulates pancreas organogenesis and endocrine cell differentiation via paracrine retinoic acid signaling
- 2016
-
Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 157:12, s. 4615-4631
-
Tidskriftsartikel (refereegranskat)abstract
- Vitamin A-derived retinoic acid (RA) signals are critical for the development of several organs, including the pancreas. However, the tissue-specific control of RA synthesis in organ and cell lineage development has only poorly been addressed in vivo. Here, we show that retinol dehydrogenase-10 (Rdh10), a key enzyme in embryonic RA production, has important functions in pancreas organogenesis and endocrine cell differentiation. Rdh10 was expressed in the developing pancreas epithelium and surrounding mesenchyme. Rdh10 null mutant mouse embryos exhibited dorsal pancreas agenesis and a hypoplastic ventral pancreas with retarded tubulogenesis and branching. Conditional disruption of Rdh10 from the endoderm caused increased mortality, reduced body weight, and lowered blood glucose levels after birth. Endodermal Rdh10 deficiency led to a smaller dorsal pancreas with a reduced density of early glucagonβ and insulinβ cells. During the secondary transition, the reduction of Neurogenin3β endocrine progenitors in the mutant dorsal pancreas accounted for fewer β-and α-cells. Changes in the expression of β-and α-cellspecific transcription factors indicated that Rdh10 might also participate in the terminal differentiation of endocrine cells. Together, our results highlight the importance of both mesenchymal andepithelialRdh10forpancreogenesisandthefirstwaveofendocrinecell differentiation.Wefurther propose a model in which the Rdh10-expressing exocrine tissue acts as an essential source ofRAsignals in the second wave of endocrine cell differentiation.
|
|
| 2. |
- Hepburn, Lucy, et al.
(författare)
-
A Spaetzle-like role for nerve growth factor beta in vertebrate immunity to Staphylococcus aureus
- 2014
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 346:6209, s. 641-646
-
Tidskriftsartikel (refereegranskat)abstract
- Many key components of innate immunity to infection are shared between Drosophila and humans. However, the fly Toll ligand Spaetzle is not thought to have a vertebrate equivalent. We have found that the structurally related cystine-knot protein, nerve growth factor β (NGFβ), plays an unexpected Spaetzle-like role in immunity to Staphylococcus aureus infection in chordates. Deleterious mutations of either human NGFβ or its high-affinity receptor tropomyosin-related kinase receptor A (TRKA) were associated with severe S. aureus infections. NGFβ was released by macrophages in response to S. aureus exoproteins through activation of the NOD-like receptors NLRP3 and NLRP4 and enhanced phagocytosis and superoxide-dependent killing, stimulated proinflammatory cytokine production, and promoted calcium-dependent neutrophil recruitment. TrkA knockdown in zebrafish increased susceptibility to S. aureus infection, confirming an evolutionarily conserved role for NGFβ-TRKA signaling in pathogen-specific host immunity.
|
|
