The X-linked acrogigantism-associated gene gpr101 is a regulator of early embryonic development and growth in zebrafish.
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ABSTRACT:
SUBMITTER: Trivellin G
PROVIDER: S-EPMC8771005 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:X-linked acrogigantism (X-LAG) is the most severe form of pituitary gigantism and is characterized by aggressive growth hormone (GH)-secreting pituitary tumors that occur in early childhood. X-LAG is associated with chromosome Xq26.3 duplications (the X-LAG locus typically includes VGLL1, CD40LG, ARHGEF6, RBMX, and GPR101) that lead to massive pituitary tumoral expression of GPR101, a novel regulator of GH secretion. The mechanism by which the duplications lead to marked pituitary misexpression of GPR101 alone was previously unclear. Using Hi-C and 4C-seq, we characterized the normal chromatin structure at the X-LAG locus. We showed that GPR101 is located within a topologically associating domain (TAD) delineated by a tissue-invariant border that separates it from centromeric genes and regulatory sequences. Next, using 4C-seq with GPR101, RBMX, and VGLL1 viewpoints, we showed that the duplications in multiple X-LAG-affected individuals led to ectopic interactions that crossed the invariant TAD border, indicating the existence of a similar and consistent mechanism of neo-TAD formation in X-LAG. We then identified several pituitary active cis-regulatory elements (CREs) within the neo-TAD and demonstrated in vitro that one of them significantly enhanced reporter gene expression. At the same time, we showed that the GPR101 promoter permits the incorporation of new regulatory information. Our results indicate that X-LAG is a TADopathy of the endocrine system in which Xq26.3 duplications disrupt the local chromatin architecture forming a neo-TAD. Rewiring GPR101-enhancer interaction within the new regulatory unit is likely to cause the high levels of aberrant expression of GPR101 in pituitary tumors caused by X-LAG.
| S-EPMC9069129 | biostudies-literature
Project description:Non-syndromic pituitary gigantism can result from AIP mutations or the recently identified Xq26.3 microduplication causing X-linked acrogigantism (XLAG). Within Xq26.3, GPR101 is believed to be the causative gene, and the c.924G?>?C (p.E308D) variant in this orphan G protein-coupled receptor has been suggested to play a role in the pathogenesis of acromegaly.We studied 153 patients (58 females and 95 males) with pituitary gigantism. AIP mutation-negative cases were screened for GPR101 duplication through copy number variation droplet digital PCR and high-density aCGH. The genetic, clinical and histopathological features of XLAG patients were studied in detail. 395 peripheral blood and 193 pituitary tumor DNA samples from acromegaly patients were tested for GPR101 variants.We identified 12 patients (10 females and 2 males; 7.8 %) with XLAG. In one subject, the duplicated region only contained GPR101, but not the other three genes in found to be duplicated in the previously reported patients, defining a new smallest region of overlap of duplications. While females presented with germline mutations, the two male patients harbored the mutation in a mosaic state. Nine patients had pituitary adenomas, while three had hyperplasia. The comparison of the features of XLAG, AIP-positive and GPR101&AIP-negative patients revealed significant differences in sex distribution, age at onset, height, prolactin co-secretion and histological features. The pathological features of XLAG-related adenomas were remarkably similar. These tumors had a sinusoidal and lobular architecture. Sparsely and densely granulated somatotrophs were admixed with lactotrophs; follicle-like structures and calcifications were commonly observed. Patients with sporadic of familial acromegaly did not have an increased prevalence of the c.924G?>?C (p.E308D) GPR101 variant compared to public databases.In conclusion, XLAG can result from germline or somatic duplication of GPR101. Duplication of GPR101 alone is sufficient for the development of XLAG, implicating it as the causative gene within the Xq26.3 region. The pathological features of XLAG-associated pituitary adenomas are typical and, together with the clinical phenotype, should prompt genetic testing.
| S-EPMC4888203 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-02-23 | GSE193114 | GEO
Project description:X-linked acrogigantism (X-LAG) is the most severe form of pituitary gigantism and is characterized by aggressive growth hormone (GH)-secreting pituitary tumors that occur in early childhood. X-LAG is associated with chromosome Xq26.3 duplications (the X-LAG locus typically includes the VGLL1, CD40LG, ARGHEF6, RBMX, and GPR101 genes) that lead to massive pituitary tumoral expression of GPR101, a novel regulator of GH secretion. In this work, we aimed to unravel the mechanism by which the duplications lead to marked pituitary misexpression of GPR101 alone. Using 4C-seq, we characterized the normal chromatin structure at the X-LAG locus. Using GPR101, RBMX, and VGLL1 viewpoints, we showed that GPR101 is located within a topologically associating domain (TAD) delineated by a tissue-invariant border that separates it from centromeric genes and regulatory sequences. Then, we showed that the duplications in multiple patients led to ectopic interactions that crossed the invariant TAD border, indicating the existence of a similar and consistent mechanism of neo-TAD formation in X-LAG. Rewiring GPR101-enhancer interaction within the new regulatory unit is likely to cause the high levels of aberrant expression of GPR101 in X-LAG pituitary.
2022-02-23 | GSE193112 | GEO
Project description:X-linked acrogigantism (X-LAG) is the most severe form of pituitary gigantism and is characterized by aggressive growth hormone (GH)-secreting pituitary tumors that occur in early childhood. X-LAG is associated with chromosome Xq26.3 duplications (the X-LAG locus typically includes the VGLL1, CD40LG, ARGHEF6, RBMX, and GPR101 genes) that lead to massive pituitary tumoral expression of GPR101, a novel regulator of GH secretion. In this work, we aimed to unravel the mechanism by which the duplications lead to marked pituitary misexpression of GPR101 alone. Using 4C-seq, we characterized the normal chromatin structure at the X-LAG locus. Using GPR101, RBMX, and VGLL1 viewpoints, we showed that GPR101 is located within a topologically associating domain (TAD) delineated by a tissue-invariant border that separates it from centromeric genes and regulatory sequences. Then, we showed that the duplications in multiple patients led to ectopic interactions that crossed the invariant TAD border, indicating the existence of a similar and consistent mechanism of neo-TAD formation in X-LAG. Rewiring GPR101-enhancer interaction within the new regulatory unit is likely to cause the high levels of aberrant expression of GPR101 in X-LAG pituitary.
2022-02-23 | GSE193113 | GEO
Project description:IntroductionEmbryonic exposure to ethanol leads to a condition of physical, behavioral, and cognitive deficiencies named fetal alcohol spectrum disorders (FASD). The most severe variations are in fetal alcohol syndrome (FAS), which is easier to diagnose and not studied in animal models. On the other side, the pFAS (partial fetal alcohol syndrome) includes cases of alcohol-related congenital disabilities and neurodevelopmental disorder with an inconclusive diagnosis. In recent years, the zebrafish has become a valuable model to study FASD and its variations.MethodsThis study characterizes the zebrafish embryonic and larval development after low and moderate ethanol concentration exposure. Fish eggs were exposed to 0.0%, 0.25%, 0.5%, and 1.0% ethanol at 24 hr postfertilization, and embryonic development was observed every 8 hr up to 120 hpf. It evaluated movements, phenotypic abnormalities, hatching, cardiac function and heartbeat frequency, larvae length at 120 hpf, and the apoptotic cells' fluorescence stained with acridine orange.ResultsEmbryonic exposure to 0.5% and 1% ethanol presented reduced body size, decreased heartbeat rate, higher numbers of apoptotic cells, and hatching time differences.ConclusionsOur results suggest any ethanol exposure during embryogenesis can be harmful and reinforces zebrafish as a suitable model for fetal alcohol spectrum disorders (FASD).
| S-EPMC8213935 | biostudies-literature
Project description:PurposeCongenital hypopituitarism (CH) can cause significant morbidity or even mortality. In the majority of patients, the etiology of CH is unknown. Understanding the etiology of CH is important for anticipation of clinical problems and for genetic counselling. Our previous studies showed that only a small proportion of cases have mutations in the known 'CH genes'. In the current project, we present the results of SNP array based copy number variant analysis in a family with unexplained congenital hypopituitarism.MethodsDNA samples of two affected brothers with idiopathic CH and their mother were simultaneously analyzed by SNP arrays for copy number variant analysis and Whole Exome Sequencing (WES) for mutation screening. DNA of the father was not available.ResultsWe found a 6 Mb duplication including GPR101 and SOX3 on the X-chromosome (Xq26.2-q27.1) in the two siblings and their mother, leading to 2 copies of this region in the affected boys and 3 copies in the mother. Duplications of GPR101 are associated with X-linked acrogigantism (the phenotypic 'opposite' of the affected brothers), whereas alterations in SOX3 are associated with X-linked hypopituitarism.ConclusionIn our patients with hypopituitarism we found a 6 Mb duplication which includes GPR101, a gene associated with X- linked gigantism, and SOX3, a gene involved in early pituitary organogenesis that is associated with variable degrees of hypopituitarism. Our findings show that in duplications containing both GPR101 and SOX3, the growth hormone deficiency phenotype is dominant. This suggests that, if GPR101 is duplicated, it might not be expressed phenotypically when early patterning of the embryonic pituitary is affected due to SOX3 duplication. These results, together with the review of the literature, shed a new light on the role of GPR101 and SOX3 in pituitary function.
| S-EPMC7966638 | biostudies-literature
Project description:The molecular mechanisms that regulate cardiomyocyte proliferation during embryonic heart growth are not completely deciphered yet. In a forward genetic N-ethyl-N-nitrosourea (ENU) mutagenesis screen, we identified the recessive embryonic-lethal zebrafish mutant line weiches herz (whz). Homozygous mutant whz embryos display impaired heart growth due to diminished embryonic cardiomyocyte proliferation resulting in cardiac hypoplasia and weak cardiac contraction. By positional cloning, we found in whz mutant zebrafish a missense mutation within the T-box 20 (Tbx20) transcription factor gene leading to destabilization of Tbx20 protein. Morpholino-mediated knock-down of Tbx20 in wild-type zebrafish embryos phenocopies whz, indicating that the whz phenotype is due to loss of Tbx20 function, thereby leading to significantly reduced cardiomyocyte numbers by impaired proliferation of heart muscle cells. Ectopic overexpression of wild-type Tbx20 in whz mutant embryos restored cardiomyocyte proliferation and heart growth. Interestingly, ectopic overexpression of Tbx20 in wild-type zebrafish embryos resulted, similar to the situation in the embryonic mouse heart, in significantly reduced proliferation rates of ventricular cardiomyocytes, suggesting that Tbx20 activity needs to be tightly fine-tuned to guarantee regular cardiomyocyte proliferation and embryonic heart growth in vivo.
| S-EPMC5132222 | biostudies-literature
Project description:Fibroblast growth factor (Fgf) signaling regulates many processes during development. In most cases, one tissue layer secretes an Fgf ligand that binds and activates an Fgf receptor (Fgfr) expressed by a neighboring tissue. Although studies have identified the roles of specific Fgf ligands during development, less is known about the requirements for the receptors. We have generated null mutations in each of the five fgfr genes in zebrafish. Considering the diverse requirements for Fgf signaling throughout development, and that null mutations in the mouse Fgfr1 and Fgfr2 genes are embryonic lethal, it was surprising that all zebrafish homozygous mutants are viable and fertile, with no discernable embryonic defect. Instead, we find that multiple receptors are involved in coordinating most Fgf-dependent developmental processes. For example, mutations in the ligand fgf8a cause loss of the midbrain-hindbrain boundary, whereas, in the fgfr mutants, this phenotype is seen only in embryos that are triple mutant for fgfr1a;fgfr1b;fgfr2, but not in any single or double mutant combinations. We show that this apparent fgfr redundancy is also seen during the development of several other tissues, including posterior mesoderm, pectoral fins, viscerocranium, and neurocranium. These data are an essential step toward defining the specific Fgfrs that function with particular Fgf ligands to regulate important developmental processes in zebrafish.
| S-EPMC6707458 | biostudies-literature
Project description:In zebrafish embryos, the maternally supplied pool of ATP is insufficient to power even the earliest of developmental events (0-3 hpf) such as oocyte-to-embryo transition (OET). The embryos generate an additional pulse (2.5 h long) of ATP (1.25-4 hpf) to achieve the embryonic ATP homeostasis. We demonstrate that the additional pulse of ATP is needed for successful execution of OET. The maternally supplied yolk lipids play a crucial role in maintaining the embryonic ATP homeostasis. In this paper, we identify the source and trafficking routes of free fatty acids (FFAs) that feed the mitochondria for synthesis of ATP. Interestingly, neither the maternally supplied pool of yolk-FFA nor the yolk-FACoA (fatty acyl coenzyme A) is used for ATP homeostasis during 0-5 hpf in zebrafish embryos. With the help of lipidomics, we explore the link between lipid droplet (LD)-mediated lipolysis and ATP homeostasis in zebrafish embryos. Until 5 hpf, the embryonic LDs undergo extensive lipolysis that generates FFAs. We demonstrate that these newly synthesized FFAs from LDs are involved in the maintenance of embryonic ATP homeostasis, rather than the FFAs/FACoA present in the yolk. Thus, the LDs are vital embryonic organelles that maintain the ATP homeostasis during early developmental stages (0-5 hpf) in zebrafish embryos. Our study highlights the important roles carried on by the LDs during the early development of the zebrafish embryos.
| S-EPMC5541346 | biostudies-literature