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Dysregulated ECM remodeling proteins lead to aberrant osteogenesis of Costello syndrome iPSCs.

ABSTRACT: Costello syndrome (CS) is an autosomal dominant disorder caused by mutations in HRAS. Although CS patients have skeletal abnormalities, the role of mutated HRAS in bone development remains unclear. Here, we use CS induced pluripotent stem cells (iPSCs) undergoing osteogenic differentiation to investigate how dysregulation of extracellular matrix (ECM) remodeling proteins contributes to impaired osteogenesis. Although CS patient-derived iPSCs develop normally to produce mesenchymal stem cells (MSCs), the resulting CS MSCs show defective osteogenesis with reduced alkaline phosphatase activity and lower levels of bone mineralization. We found that hyperactivation of SMAD3 signaling during the osteogenic differentiation of CS MSCs leads to aberrant expression of ECM remodeling proteins such as MMP13, TIMP1, and TIMP2. CS MSCs undergoing osteogenic differentiation also show reduced β-catenin signaling. Knockdown of TIMPs permits normal differentiation of CS MSCs into osteoblasts and enhances β-catenin signaling in a RUNX2-independent manner. Thus, this study demonstrates that enhanced TIMP expression induced by hyperactivated SMAD3 signaling impairs the osteogenic development of CS MSCs via an inactivation of β-catenin signaling.

SUBMITTER: Choi JB

PROVIDER: S-EPMC8365028 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Expression data to investigate Costello syndrome using human iPSCs differentiated into astroglial progenitors and astrocytes

2014-12-16 | GSE64194 | GEO

Expression data to investigate Costello syndrome using human iPSCs differentiated into astroglial progenitors and astrocytes

Project description:We used microarrays to compare gene expression between three HRAS-wild type lines (13, 162d, 165d) and three HRAS-G12S mutant lines (7, 8, 16). Arrays were conducted in all lines from iPSC-derived astroglial progenitors at 8 weeks of differentiation, and in wild-type astrocyte lines at 28 weeks of differentiation. Cells of the astroglial lineage were generated for RNA extraction and hybridization on Affymetrix Human 1.0 ST microarrays. At each stage, cells were plated as a monolayer and treated with 10ng/ml of CNTF for one week before extraction.

2014-12-16 | E-GEOD-64194 | biostudies-arrayexpress

Craniofacial and dental development in Costello syndrome.

Project description:Costello syndrome (CS) is a RASopathy characterized by a wide range of cardiac, musculoskeletal, dermatological, and developmental abnormalities. The RASopathies are defined as a group of syndromes caused by activated Ras/mitogen-activated protein kinase (MAPK) signaling. Specifically, CS is caused by activating mutations in HRAS. Although receptor tyrosine kinase (RTK) signaling, which is upstream of Ras/MAPK, is known to play a critical role in craniofacial and dental development, the craniofacial and dental features of CS have not been systematically defined in a large group of individuals. In order to address this gap in our understanding and fully characterize the CS phenotype, we evaluated the craniofacial and dental phenotype in a large cohort (n = 41) of CS individuals. We confirmed that the craniofacial features common in CS include macrocephaly, bitemporal narrowing, convex facial profile, full cheeks, and large mouth. Additionally, CS patients have a characteristic dental phenotype that includes malocclusion with anterior open bite and posterior crossbite, enamel hypo-mineralization, delayed tooth development and eruption, gingival hyperplasia, thickening of the alveolar ridge, and high palate. Comparison of the craniofacial and dental phenotype in CS with other RASopathies, such as cardio-facio-cutaneous syndrome (CFC), provides insight into the complexities of Ras/MAPK signaling in human craniofacial and dental development.

| S-EPMC4115793 | biostudies-literature

Dysregulated cholesterol metabolism, aberrant excitability and altered cell cycle of astrocytes in fragile X syndrome.

Project description:Fragile X syndrome (FXS), the most prevalent heritable form of intellectual disability, is caused by the transcriptional silencing of the FMR1 gene. While neuronal contribution to FXS has been extensively studied in both animal and human-based models of FXS, the roles of astrocytes, a type of glial cells in the brain, are largely unknown. Here, we generated a human-based FXS model via differentiation of astrocytes from human-induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) and characterized their development, function, and proteomic profiles. We identified shortened cell cycle, enhanced Ca2+ signaling, impaired sterol biosynthesis, and pervasive alterations in the proteome of FXS astrocytes. Our work identified astrocytic impairments that could contribute to the pathogenesis of FXS and highlight astrocytes as a novel therapeutic target for FXS treatment.

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Dysregulation of astrocyte extracellular signaling in Costello syndrome.

Project description:Astrocytes produce an assortment of signals that promote neuronal maturation according to a precise developmental timeline. Is this orchestrated timing and signaling altered in human neurodevelopmental disorders? To address this question, the astroglial lineage was investigated in two model systems of a developmental disorder with intellectual disability caused by mutant Harvey rat sarcoma viral oncogene homolog (HRAS) termed Costello syndrome: mutant HRAS human induced pluripotent stem cells (iPSCs) and transgenic mice. Human iPSCs derived from patients with Costello syndrome differentiated to astroglia more rapidly in vitro than those derived from wild-type cell lines with normal HRAS, exhibited hyperplasia, and also generated an abundance of extracellular matrix remodeling factors and proteoglycans. Acute treatment with a farnesyl transferase inhibitor and knockdown of the transcription factor SNAI2 reduced expression of several proteoglycans in Costello syndrome iPSC-derived astrocytes. Similarly, mice in which mutant HRAS was expressed selectively in astrocytes exhibited experience-independent increased accumulation of perineuronal net proteoglycans in cortex, as well as increased parvalbumin expression in interneurons, when compared to wild-type mice. Our data indicate that astrocytes expressing mutant HRAS dysregulate cortical maturation during development as shown by abnormal extracellular matrix remodeling and implicate excessive astrocyte-to-neuron signaling as a possible drug target for treating mental impairment and enhancing neuroplasticity.

| S-EPMC4474402 | biostudies-literature

Treatment of Dystonia Using Trihexyphenidyl in Costello Syndrome.

Project description:Costello syndrome (CS), a rare syndrome with multisystemic involvement inherited as a dominant trait, is characterized by developmental delay, coarse facial appearance, cardiac defects including hypertrophic cardiomyopathy, skin abnormalities, brain complications, and a predisposition to certain malignancies. The musculoskeletal system is particularly affected in CS, with peculiar orthopedic anomalies that impact posture and gait. Dystonia has been recently documented to contribute to abnormal postures and musculoskeletal anomalies characterizing CS, suggesting the possible use of pharmacological treatments to treat these complications. We report the case of a child affected by CS displaying a particularly severe musculoskeletal involvement with dystonic posture especially in the arms and legs. The Movement Disorder-Childhood Rating Scale (MD-CRS) and a gait analysis were used to assess clinical patterns of hyperkinetic movement disorder and dystonia. The child was further treated with trihexyphenidyl for six months with a final dosage of 14 mg. MD-CRS and gait analysis assessments provided evidence for a significant improvement of posture and the related musculoskeletal problems with no side effects. Our preliminary study report provides first evidence that pharmacological anti-dystonia treatment significantly improves movement and posture disorders in patients with CS. Further studies enrolling larger cohorts of patients should be performed to validate these preliminary observations.

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Fatal leukodystrophy in Costello syndrome: a case report.

Project description:BackgroundCostello syndrome (CS) is a rare genetic condition characterized by dysregulation of the signaling pathway, phenotypic alteration due to fetal macrosomia or growth retardation, facial abnormalities, loose skin, cardiovascular abnormalities, and a variable degree of intellectual disability.Case presentationWe describe the case of a 20-month-old male patient with fetal macrosomia and polyhydramnios, presenting psychomotor development delay and growth limitation during the first months of life. CS was diagnosed at four months of age after detecting a variant of the HRAS gene c.35G > C (p.G12A). A clinical description of his condition was recorded throughout his life, including cardiovascular diseases, endocrine disorders, and recurrent infections. At 20 months of age, after presenting events of marked hypotonia and generalized seizures, brain magnetic resonance revealed symmetrical lesions of the infra- and supratentorial white matter in both cerebral hemispheres, which resulted in the diagnosis of cerebral leukodystrophy. The patient had a rapid and progressive deterioration that eventually led to death.ConclusionsThis is the first report of a case of CS in Peru. In addition, this is a case that presented with multisystemic conditions culminating in leukodystrophy, which is a rare event according to the literature.

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Project description:Noonan syndrome (NS) is a genetic disorder mainly caused by gain-of-function mutations of SHP2. Although diverse neurological manifestations are commonly diagnosed in NS patients, mechanisms on how the SHP2 mutation induces the neurodevelopmental defects remain elusive. Here, we report that cortical organoids (NS-COs) derived from NS-induced pluripotent stem cells (iPSCs) exhibit developmental abnormalities, especially in excitatory neurons (ENs). Although NS-COs normally develop in appearance, single-cell transcriptomic analysis represented increment of EN population and overexpression of cortical layer markers in NS-COs. Surprisingly, EN subpopulation co-expressing upper layer marker SATB2 and deep layer maker CTIP2 was enriched in NS-COs during the cortical development. In parallel with the developmental disruptions, NS-COs also exhibited reduced synaptic connectivity. Collectively, our findings suggest that perturbed cortical layer identity and impeded neuronal connectivity account for the neurological manifestations of NS.

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