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1.
Elife ; 82019 09 10.
Article in English | MEDLINE | ID: mdl-31502954

ABSTRACT

The segregation of cells with distinct regional identity underlies formation of a sharp border, which in some tissues serves to organise a boundary signaling centre. It is unclear whether or how border sharpness is coordinated with induction of boundary-specific gene expression. We show that forward signaling of EphA4 is required for border sharpening and induction of boundary cells in the zebrafish hindbrain, which we find both require kinase-dependent signaling, with a lesser input of PDZ domain-dependent signaling. We find that boundary-specific gene expression is regulated by myosin II phosphorylation, which increases actomyosin contraction downstream of EphA4 signaling. Myosin phosphorylation leads to nuclear translocation of Taz, which together with Tead1a is required for boundary marker expression. Since actomyosin contraction maintains sharp borders, there is direct coupling of border sharpness to boundary cell induction that ensures correct organisation of signaling centres.


Subject(s)
Actomyosin/metabolism , Brain/embryology , Gene Expression Regulation, Developmental , Receptor, EphA4/metabolism , Signal Transduction , Acyltransferases , Animals , DNA-Binding Proteins/metabolism , Nuclear Proteins/metabolism , Phosphorylation , Protein Processing, Post-Translational , TEA Domain Transcription Factors , Transcription Factors/metabolism , Zebrafish , Zebrafish Proteins/metabolism
2.
Dev Cell ; 45(5): 606-620.e3, 2018 06 04.
Article in English | MEDLINE | ID: mdl-29731343

ABSTRACT

The patterning of tissues to form subdivisions with distinct and homogeneous regional identity is potentially disrupted by cell intermingling. Transplantation studies suggest that homogeneous segmental identity in the hindbrain is maintained by identity switching of cells that intermingle into another segment. We show that switching occurs during normal development and is mediated by feedback between segment identity and the retinoic acid degrading enzymes, cyp26b1 and cyp26c1. egr2, which specifies the segmental identity of rhombomeres r3 and r5, underlies the lower expression level of cyp26b1 and cyp26c1 in r3 and r5 compared with r2, r4, and r6. Consequently, r3 or r5 cells that intermingle into adjacent segments encounter cells with higher cyp26b1/c1 expression, which we find is required for downregulation of egr2b expression. Furthermore, egr2b expression is regulated in r2, r4, and r6 by non-autonomous mechanisms that depend upon the number of neighbors that express egr2b. These findings reveal that a community regulation of retinoid signaling maintains homogeneous segmental identity.


Subject(s)
Body Patterning/drug effects , Cell Lineage/drug effects , Embryo, Nonmammalian/physiology , Rhombencephalon/physiology , Tretinoin/pharmacology , Zebrafish Proteins/metabolism , Zebrafish/physiology , Animals , Antineoplastic Agents/pharmacology , Cellular Reprogramming , Embryo, Nonmammalian/cytology , Gene Expression Regulation, Developmental/drug effects , Neural Crest/cytology , Neural Crest/physiology , Rhombencephalon/cytology , Rhombencephalon/drug effects , Signal Transduction , Zebrafish/growth & development , Zebrafish Proteins/genetics
3.
Curr Top Dev Biol ; 117: 581-96, 2016.
Article in English | MEDLINE | ID: mdl-26970002

ABSTRACT

The subdivision of tissues into sharply demarcated regions with distinct and homogenous identity is an essential aspect of embryonic development. Along the anteroposterior axis of the vertebrate nervous system, this involves signaling which induces spatially restricted expression of transcription factors that specify regional identity. The spatial expression of such transcription factors is initially imprecise, with overlapping expression of genes that specify distinct identities, and a ragged border at the interface of adjacent regions. This pattern becomes sharpened by establishment of mutually exclusive expression of transcription factors, and by cell segregation that underlies formation of a straight border. In this review, we discuss studies of the vertebrate hindbrain which have revealed how discrete regional identity is established, the roles of Eph-ephrin signaling in cell segregation and border sharpening, and how cell identity and cell segregation are coupled.


Subject(s)
Body Patterning , Cell Separation , Ephrins/metabolism , Rhombencephalon/cytology , Vertebrates/growth & development , Animals , Gene Expression Regulation, Developmental , Rhombencephalon/metabolism , Signal Transduction , Vertebrates/metabolism
4.
Am J Physiol Lung Cell Mol Physiol ; 302(6): L541-54, 2012 Mar 15.
Article in English | MEDLINE | ID: mdl-22198906

ABSTRACT

Most patients with familial pulmonary arterial hypertension (FPAH) carry mutations in the bone morphogenic protein receptor 2 gene (BMPR2). Yet carriers have only a 20% risk of disease, suggesting that other factors influence penetrance. Thrombospondin-1 (TSP1) regulates activation of TGF-ß and inhibits endothelial and smooth muscle cell proliferation, pathways coincidentally altered in pulmonary arterial hypertension (PAH). To determine whether a subset of FPAH patients also have mutations in the TSP1 gene (THBS1) we resequenced the type I repeats of THBS1 encoding the TGF-ß regulation and cell growth inhibition domains in 60 FPAH probands, 70 nonfamilial PAH subjects, and in large control groups. We identified THBS1 mutations in three families: a novel missense mutation in two (Asp362Asn), and an intronic mutation in a third (IVS8+255 G/A). Neither mutation was detected in population controls. Mutant 362Asn TSP1 had less than half of the ability of wild-type TSP1 to activate TGF-ß. Mutant 362Asn TSP1 also lost the ability to inhibit growth of pulmonary arterial smooth muscle cells and was over threefold less effective at inhibiting endothelial cell growth. The IVS8+255 G/A mutation decreased and/or eliminated local binding of the transcription factors SP1 and MAZ but did not affect RNA splicing. These novel mutations implicate THBS1 as a modifier gene in FPAH. These THBS1 mutations have implications in the genetic evaluation of FPAH patients. However, since FPAH is rare, these data are most relevant as evidence for the importance of TSP1 in pulmonary vascular homeostasis. Further examination of THBS1 in the pathogenesis of PAH is warranted.


Subject(s)
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Hypertension, Pulmonary/genetics , Hypertension, Pulmonary/metabolism , Mutation, Missense , Binding Sites , Cell Growth Processes/genetics , Cells, Cultured , Cohort Studies , Conserved Sequence , DNA-Binding Proteins/metabolism , Endothelial Cells/metabolism , Familial Primary Pulmonary Hypertension , Female , Humans , Introns , Male , Myocytes, Smooth Muscle/metabolism , Polymorphism, Genetic , Protein Binding , Pulmonary Artery/metabolism , RNA Splicing/genetics , Sp1 Transcription Factor/metabolism , Transcription Factors/metabolism , Transforming Growth Factor beta/metabolism
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