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1.
Proc Natl Acad Sci U S A ; 119(50): e2211690119, 2022 12 13.
Article in English | MEDLINE | ID: mdl-36469778

ABSTRACT

In the zebrafish retina, Müller glia (MG) can regenerate retinal neurons lost to injury or disease. Even though zebrafish MG share structure and function with those of mammals, only in zebrafish do MG function as retinal stem cells. Previous studies suggest dying neurons, microglia/macrophage, and T cells contribute to MG's regenerative response [White et al., Proc. Natl. Acad. Sci. U.S.A. 114, E3719 (2017); Hui et al., Dev. Cell 43, 659 (2017)]. Although MG end-feet abut vascular endothelial (VE) cells to form the blood-retina barrier, a role for VE cells in retina regeneration has not been explored. Here, we report that MG-derived Vegfaa and Pgfa engage Flt1 and Kdrl receptors on VE cells to regulate MG gene expression, Notch signaling, proliferation, and neuronal regeneration. Remarkably, vegfaa and pgfa expression is regulated by microglia/macrophages, while Notch signaling in MG is regulated by a Vegf-dll4 signaling system in VE cells. Thus, our studies link microglia/macrophage, MG, and VE cells in a multicomponent signaling pathway that controls MG reprogramming and proliferation.


Subject(s)
Zebrafish Proteins , Zebrafish , Animals , Zebrafish/metabolism , Zebrafish Proteins/metabolism , Animals, Genetically Modified , Endothelial Cells/metabolism , Nerve Regeneration/physiology , Neuroglia/metabolism , Retina/metabolism , Regeneration/physiology , Signal Transduction , Cell Proliferation/physiology , Ependymoglial Cells/metabolism , Mammals/metabolism
2.
Glia ; 69(12): 2882-2898, 2021 12.
Article in English | MEDLINE | ID: mdl-34415582

ABSTRACT

Zebrafish Müller glia (MG) respond to retinal injury by suppressing Notch signaling and producing progenitors for retinal repair. A certain threshold of injury-derived signal must be exceeded in order to engage MG in a regenerative response (MG's injury-response threshold). Pan-retinal Notch inhibition expands the zone of injury-responsive MG at the site of focal injury, suggesting that Notch signaling regulates MG's injury-response threshold. We found that Notch signaling enhanced chromatin accessibility and gene expression at a subset of regeneration-associated genes in the uninjured retina. Two Notch effector genes, hey1 and id2b, were identified that reflect bifurcation of the Notch signaling pathway, and differentially regulate MG's injury-response threshold and proliferation of MG-derived progenitors. Furthermore, Notch signaling component gene repression in the injured retina suggests a role for Dll4, Dlb, and Notch3 in regulating Notch signaling in MG and epistasis experiments confirm that the Dll4/Dlb-Notch3-Hey1/Id2b signaling pathway regulates MG's injury-response threshold and proliferation.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors , Neuroglia , Receptors, Notch , Zebrafish Proteins , Zebrafish , Animals , Cell Proliferation/physiology , Neuroglia/metabolism , Receptors, Notch/metabolism , Retina/metabolism , Signal Transduction , Zebrafish/genetics , Zebrafish/metabolism , Zebrafish Proteins/metabolism
3.
PLoS Genet ; 17(8): e1009685, 2021 08.
Article in English | MEDLINE | ID: mdl-34343194

ABSTRACT

Gap junction (GJ) proteins, the primary constituents of GJ channels, are conserved determinants of patterning. Canonically, a GJ channel, made up of two hemi-channels contributed by the neighboring cells, facilitates transport of metabolites/ions. Here we demonstrate the involvement of GJ proteins during cuboidal to squamous epithelial transition displayed by the anterior follicle cells (AFCs) from Drosophila ovaries. Somatically derived AFCs stretch and flatten when the adjacent germline cells start increasing in size. GJ proteins, Innexin2 (Inx2) and Innexin4 (Inx4), functioning in the AFCs and germline respectively, promote the shape transformation by modulating calcium levels in the AFCs. Our observations suggest that alterations in calcium flux potentiate STAT activity to influence actomyosin-based cytoskeleton, possibly resulting in disassembly of adherens junctions. Our data have uncovered sequential molecular events underlying the cuboidal to squamous shape transition and offer unique insight into how GJ proteins expressed in the neighboring cells contribute to morphogenetic processes.


Subject(s)
Connexins/metabolism , Drosophila Proteins/metabolism , Drosophila/growth & development , Epithelial Cells/physiology , Ovarian Follicle/physiology , Actomyosin/metabolism , Animals , Body Patterning , Calcium Signaling , Connexins/genetics , Cytoskeleton/metabolism , Drosophila/metabolism , Drosophila Proteins/genetics , Epithelial Cells/metabolism , Female , Morphogenesis , Ovarian Follicle/metabolism
4.
PLoS Genet ; 13(1): e1006542, 2017 01.
Article in English | MEDLINE | ID: mdl-28114410

ABSTRACT

Intercellular communication mediated by gap junction (GJ) proteins is indispensable during embryogenesis, tissue regeneration and wound healing. Here we report functional analysis of a gap junction protein, Innexin 2 (Inx2), in cell type specification during Drosophila oogenesis. Our data reveal a novel involvement of Inx2 in the specification of Border Cells (BCs), a migratory cell type, whose identity is determined by the cell autonomous STAT activity. We show that Inx2 influences BC fate specification by modulating STAT activity via Domeless receptor endocytosis. Furthermore, detailed experimental analysis has uncovered that Inx2 also regulates a calcium flux that transmits across the follicle cells. We propose that Inx2 mediated calcium flux in the follicle cells stimulates endocytosis by altering Dynamin (Shibire) distribution which is in turn critical for careful calibration of STAT activation and, thus for BC specification. Together our data provide unprecedented molecular insights into how gap junction proteins can regulate cell-type specification.


Subject(s)
Calcium/metabolism , Connexins/metabolism , Drosophila Proteins/metabolism , Drosophila/genetics , Oogenesis , Animals , Connexins/genetics , Drosophila/growth & development , Drosophila Proteins/genetics , Dynamins/genetics , Dynamins/metabolism , Endocytosis , Female , Ovarian Follicle/cytology , Ovarian Follicle/metabolism , Receptors, Interleukin/genetics , Receptors, Interleukin/metabolism , STAT Transcription Factors/genetics , STAT Transcription Factors/metabolism
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