Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
Genetics ; 202(1): 123-39, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26434722

ABSTRACT

Neural tube defects including spina bifida are common and severe congenital disorders. In mice, mutations in more than 200 genes can result in neural tube defects. We hypothesized that this large gene set might include genes whose homologs contribute to morphogenesis in diverse animals. To test this hypothesis, we screened a set of Caenorhabditis elegans homologs for roles in gastrulation, a topologically similar process to vertebrate neural tube closure. Both C. elegans gastrulation and vertebrate neural tube closure involve the internalization of surface cells, requiring tissue-specific gene regulation, actomyosin-driven apical constriction, and establishment and maintenance of adhesions between specific cells. Our screen identified several neural tube defect gene homologs that are required for gastrulation in C. elegans, including the transcription factor sptf-3. Disruption of sptf-3 in C. elegans reduced the expression of early endodermally expressed genes as well as genes expressed in other early cell lineages, establishing sptf-3 as a key contributor to multiple well-studied C. elegans cell fate specification pathways. We also identified members of the actin regulatory WAVE complex (wve-1, gex-2, gex-3, abi-1, and nuo-3a). Disruption of WAVE complex members reduced the narrowing of endodermal cells' apical surfaces. Although WAVE complex members are expressed broadly in C. elegans, we found that expression of a vertebrate WAVE complex member, nckap1, is enriched in the developing neural tube of Xenopus. We show that nckap1 contributes to neural tube closure in Xenopus. This work identifies in vivo roles for homologs of mammalian neural tube defect genes in two manipulable genetic model systems.


Subject(s)
Caenorhabditis elegans/genetics , Morphogenesis/genetics , Neural Tube/embryology , Animals , Caenorhabditis elegans/embryology , Caenorhabditis elegans Proteins/genetics , Cell Cycle , Cell Membrane , Embryonic Development/genetics , Endoderm/metabolism , Gastrulation/genetics , Genes, Helminth , Humans , RNA Interference , RNA, Helminth , Sequence Analysis, RNA , Transcription Factors/genetics , Vertebrates/embryology , Vertebrates/genetics , Xenopus laevis
2.
Nat Commun ; 4: 2910, 2013.
Article in English | MEDLINE | ID: mdl-24335996

ABSTRACT

Although hypertension is a worldwide health issue, an incomplete understanding of its aetiology has hindered our ability to treat this complex disease. Here we identify arhgap42 (also known as GRAF3) as a Rho-specific GAP expressed specifically in smooth muscle cells (SMCs) in mice and humans. We show that GRAF3-deficient mice exhibit significant hypertension and increased pressor responses to angiotensin II and endothelin-1; these effects are prevented by treatment with the Rho-kinase inhibitor, Y27632. RhoA activity and myosin light chain phosphorylation are elevated in GRAF3-depleted SMCs in vitro and in vivo, and isolated vessel segments from GRAF3-deficient mice show increased contractility. Taken together, our data indicate that GRAF3-mediated inhibition of RhoA activity in vascular SMCs is necessary for maintaining normal blood pressure homoeostasis. Moreover, these findings provide a potential mechanism for a hypertensive locus recently identified within arhgap42 and provide a foundation for the future development of innovative hypertension therapies.


Subject(s)
GTPase-Activating Proteins/metabolism , Hypertension/physiopathology , Muscle, Smooth, Vascular/metabolism , Amino Acid Sequence , Angiotensin II/pharmacology , Animals , Aorta/metabolism , Blood Pressure/genetics , Blood Vessels/physiopathology , Cells, Cultured , Female , GTPase-Activating Proteins/genetics , Humans , Hypertension/drug therapy , Hypertension/etiology , Hypertension/genetics , In Vitro Techniques , Male , Mice , Mice, Mutant Strains , Molecular Sequence Data , Muscle, Smooth, Vascular/physiopathology , Myocytes, Smooth Muscle/metabolism , Myosin Light Chains/metabolism , Phosphorylation , Rats , rhoA GTP-Binding Protein/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...