Search results for DHH

Showing 14 results out of 19

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Species

Types

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Protein (5 results from a total of 10)

Identifier: R-HSA-5362781
Species: Homo sapiens
Compartment: extracellular region
Primary external reference: UniProt: DHH: O43323
Identifier: R-HSA-5362388
Species: Homo sapiens
Compartment: endoplasmic reticulum lumen
Primary external reference: UniProt: DHH: O43323
Identifier: R-HSA-5358275
Species: Homo sapiens
Compartment: endoplasmic reticulum lumen
Primary external reference: UniProt: O43323
Identifier: R-HSA-5358291
Species: Homo sapiens
Compartment: endoplasmic reticulum lumen
Primary external reference: UniProt: O43323
Identifier: R-HSA-5358287
Species: Homo sapiens
Compartment: endoplasmic reticulum lumen
Primary external reference: UniProt: O43323

DNA Sequence (1 results from a total of 1)

Identifier: R-HSA-9692094
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: ENSEMBL: ENSG00000139549

Reaction (3 results from a total of 3)

Identifier: R-HSA-9692146
Species: Homo sapiens
Compartment: nucleoplasm, extracellular region
The DHH gene is transcribed to yield mRNA and the mRNA is translated to yield DHH protein (Rahmoun et al. 2017 and inferred from mouse homologs). Transcription of DHH is directly activated by SOX9 (inferred from mouse homologs). DHH is secreted from pre-Sertoli cells (Rahmoun et al. 2017 and inferred from mouse homologs) and acts via the PTCH1 receptor to regulate testis development.
Identifier: R-HSA-9692150
Species: Homo sapiens
Compartment: nucleoplasm
SOX9 binds the promoter of the DHH gene (inferred from mouse homologs).
Identifier: R-HSA-5483229
Species: Homo sapiens
Compartment: endoplasmic reticulum membrane
A G287V loss-of-function mutation in HHAT was identified in a rare case of Syndromic 46, XY Disorder of Sex Development, which results in testis dysgenesis. The mutation does not affect the stability, localization or expression level of the HHAT when expressed from a plasmid in COS-1 cells, but the mutant protein is unable to palmitoylate SHH or DHH in an in vitro assay and expression of the HHAT loss-of-function gene in mice recapitulates the phenotypes seen in the human patient (Callier et al, 2014). These findings support a role for DHH signaling in testis development, consistent with earlier reports (Umehara et al, 2000; Canto et al, 2004; Canto et al, 2005; Das et al, 2011).

Complex (1 results from a total of 1)

Identifier: R-HSA-9692116
Species: Homo sapiens
Compartment: nucleoplasm

Chemical Compound (1 results from a total of 1)

Identifier: R-ALL-2162278
Compartment: mitochondrial matrix
Primary external reference: ChEBI: 3-hexaprenyl-4,5-dihydroxybenzoic acid: 18081

Pathway (3 results from a total of 3)

Identifier: R-HSA-5387390
Species: Homo sapiens
Hh signaling is required for a number of developmental processes, and mutations that disrupt the normal processing and biogenesis of Hh ligand can result in neonatal abnormalities. SHH is one of a number of genes that have been associated with the congenital disorder holoprosencephaly, which causes abnormalities in brain and craniofacial development (Roessler et al, 2009; reviewed in Roessler and Muenke, 2011). SHH variants associated with the condition affect the autocatalytic processing of the precursor and dramatically impair the production of the secreted active Hh-Np, abrogating signaling (reviewed in Pan et al, 2013). Aberrant Hh signaling is also associated with gondal dysgenesis syndromes in which palmitoylation of DHH is abrogated by mutation of the acyltransferase HHAT (Callier et al, 2014).
Identifier: R-HSA-5358346
Species: Homo sapiens
Mammalian genomes encode three Hedgehog ligands, Sonic Hedgehog (SHH), Indian Hedgehog (IHH) and Desert Hedgehog (DHH). These secreted morphogens can remain associated with lipid rafts on the surface of the secreting cell and affect developmental processes in adjacent cells. Alternatively, they can be released by proteolysis or packaging into vesicles or lipoprotein particles and dispersed to act on distant cells. SHH activity is required for organization of the limb bud, notochord and neural plate, IHH regulates bone and cartilage development and is partially redundant with SHH, and DHH contributes to germ cell development in the testis and formation of the peripheral nerve sheath (reviewed in Pan et al, 2013).

Despite divergent biological roles, all Hh ligands are subject to proteolytic processing and lipid modification during transit to the surface of the secreting cell (reviewed in Gallet, 2011). Precursor Hh undergoes autoproteolytic cleavage mediated by the C-terminal region to yield an amino-terminal peptide Hh-Np (also referred to as Hh-N) (Chen et al, 2011). No other well defined role for the C-terminal region of Hh has been identified, and the secreted Hh-Np is responsible for all Hh signaling activity. Hh-Np is modified with cholesterol and palmitic acid during transit through the secretory system, and both modifications contribute to the activity of the ligand (Porter et al, 1996; Pepinsky et al, 1998; Chamoun et al, 2001).

At the cell surface, Hh-Np remains associated with the secreting cell membrane by virtue of its lipid modifications, which promote clustering of Hh-Np into lipid rafts (Callejo et al, 2006; Peters et al, 2004). Long range dispersal of Hh-Np depends on the untethering of the ligand from the membrane through a variety of mechanisms. These include release of monomers through the combined activity of the transmembrane protein Dispatched (DISP2) and the secreted protein SCUBE2, assembly into soluble multimers or apolipoprotein particles or release on the surface of exovesicles (Vyas et al, 2008; Tukachinsky et al, 2012; Chen 2004; Zeng et al, 2001; reviewed in Briscoe and Therond, 2013).
Identifier: R-HSA-9690406
Species: Homo sapiens
In humans, primordial germ cells (PGCs) are specified about 2 weeks after fertilization, a time before gastrulation (reviewed in Svingen and Koopman 2013, Mäkelä et al. 2019). PGCs are initially located extraembryonically and then migrate to colonize the gonadal ridges (genital ridges) of the embryo during the fifth week after fertilization. At this time, either ovaries and testes can originate from the gonadal ridges. That is, the cells of the gonadal ridges are initially bipotential and remain bipotential until about 42 days after conception, when transient expression of the SRY gene located on the Y chromosome in male embryos is initiated in some somatic cells of the gonadal primordium (reviewed in Sekido and Lovell-Badge 2013, Barrionuevo et al. 2013, Svingen et al. 2013, Mäkelä et al. 2019).
The transcription factors WT1, GATA4, ZFPM2 (FOG2), and the nuclear receptor NR5A1 (SF1) activate transcription of SRY (Shimamura et al. 1997, Hossain and Saunders 2001, De Santa Barbara et al. 2001, Miyamoto et al. 2008, and inferred from mouse homologs). SRY and NR5A1 then activate transcription of SOX9, one of the master regulators of testis development and maintenance (Knower et al. 2011, Croft et al. 2018, inferred from mouse homologs, reviewed in Gonen and Lovell-Badge 2019). Regulation of genes by SRY and then, when expression of SRY decreases, by SOX9 causes the specification of Sertoli cells that further organize formation of the testis by encasing the primordial germ cells in protocords, which then form fully developed testis cords.
SOX9 directly activates its own promoter to maintain SOX9 expression through development and into adulthood (Croft et al. 2018, and inferred from mouse homologs). SOX9 and GATA4 directly activate DMRT1 (inferred from mouse homologs), which maintains testis specification by maintaining expression of SOX9 and other testis-related genes. DMRT1 also acts to suppress ovarian specification by binding and repressing FOXL2 and WNT4 genes (inferred from mouse homologs). SOX9 directly activates FGF9 (inferred from mouse homologs), which acts via FGFR2 to maintain SOX9 expression, and PTGDS (inferred from mouse homologs), which converts Prostaglandin H2 to Prostaglandin D2, a critical hormone-like lipid that recruits supporting cells to Sertoli cells and acts indirectly to maintain SOX9 expression. SOX9, NR5A1, and GATA4 directly activate AMH (De Santa Barbara et al. 1998, and inferred from mouse homologs), an extracellular signaling molecule which causes regression of the Muellerian duct of the female reproductive system. SOX9 also directly activates many other genes, including DHH (Rahmoun et al. 2017, and inferred from mouse homologs), an intercellular signaling molecule required for testis formation.
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