Suppressor of Fused Controls Mid-Hindbrain Patterning and Cerebellar Morphogenesis via GLI3 Repressor

Kim, Jinny J.; Gill, Paul; Rotin, Lianne E; Eede, Matthijs van; Henkelman, R. Mark; Hui, Chi‐chung; Rosenblum, Norman D.

doi:10.1523/jneurosci.2166-10.2011

Cited by 37 publications

(48 citation statements)

References 35 publications

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“…In contrast, inside the cerebellar anlage, Shh secretion by Purkinje neurons is not initiated until E18.5 (Corrales et al, 2004; Fuccillo et al, 2006; Huang et al, 2010; Kim et al, 2011; Lewis et al, 2004). Unexpectedly, we detected increased levels of Shh signaling targets ( Gli1 and Ptch1 transcripts) and CyclinD1 in the EGL and outer uRL of Nestin-Gpr161 cko mice compared with the littermate controls at E15.5 by in situ hybridization and immunofluorescence analysis (Figures 5N and 5O).…”

Section: Resultsmentioning

confidence: 95%

“…Sonic hedgehog (Shh) is a critical mitogen regulating GC progenitor proliferation (Dahmane and Ruiz i Altaba, 1999; Wallace, 1999; Wechsler-Reya and Scott, 1999). However, Shh is secreted by Purkinje neurons, starting only from E18.5, resulting in a postnatal growth spurt of GC progenitors (Corrales et al, 2004; Fuccillo et al, 2006; Huang et al, 2010; Kim et al, 2011; Lewis et al, 2004). The factors that regulate the generation and maintenance of GC progenitor pools during embryogenesis in the low Shh environment, and whether basal suppression of Shh signaling plays any role during these critical developmental stages, are not known.…”

Section: Introductionmentioning

confidence: 99%

“…Mutations in Suppressor of fused ( SUFU ), a negative regulator that functions by restraining cytoplasmic Gli3 and promoting Gli3R processing, have been reported in SHH-MBs (Taylor et al, 2002). However, early embryonic deletion of Sufu in the cerebellum did not exhibit tumorigenesis (Kim et al, 2011), whereas heterozygotes developed Shh-MBs only in a p53 -null background (Lee et al, 2007). We recently identified the cilium-localized orphan G-protein-coupled receptor (GPCR) Gpr161 to be a negative regulator of Shh signaling during neural tube development (Mukhopadhyay et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis

et al. 2018

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SUMMARY Sonic hedgehog (Shh) determines cerebellar granule cell (GC) progenitor proliferation and medulloblastoma pathogenesis. However, the pathways regulating GC progenitors during embryogenesis before Shh production by Purkinje neurons and their roles in tumorigenesis remain unclear. The cilium-localized G-protein-coupled receptor Gpr161 suppresses Shh-mediated signaling in the neural tube. Here, by deleting Gpr161 in mouse neural stem cells or GC progenitors, we establish Gpr161 as a tumor suppressor in Shh subtype medulloblastoma. Irrespective of Shh production in the cerebellum, Gpr161 deletion increased downstream activity of the Shh pathway by restricting Gli3-mediated repression, causing more extensive generation and proliferation of GC progenitors. Moreover, earlier deletion of Gpr161 during embryogenesis increased tumor incidence and severity. GC progenitor overproduction during embryogenesis from Gpr161 deletion was cilium dependent, unlike normal development. Low GPR161 expression correlated with poor survival of SHH subtype medulloblastoma patients. Gpr161 restricts GC progenitor production by preventing premature and Shh-dependent pathway activity, highlighting the importance of basal pathway suppression in tumorigenesis.

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Section: Resultsmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis

et al. 2018

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“…32 Limb-specific conditional deletion of Sufu results in polydactyly due to a block in Gli3R processing, 33,34 whereas mouse embryos with conditional knock-out of Sufu in the mid-hindbrain show altered morphology of the brainstem and cerebellum and delayed differentiation and abnormal migration of most cerebellar cell types. 35 Here, we show that germline hypomorphic variants of SUFU cause deregulation of the SHH pathway, resulting in recessive stereotypical developmental defects of the CNS and limbs which share peculiar features with both SHH-related disorders and with ciliopathies such as JS.…”

Section: Introductionmentioning

confidence: 82%

Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects

Mori

Romani²,

D’Arrigo

et al. 2017

The American Journal of Human Genetics

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The Sonic Hedgehog (SHH) pathway is a key signaling pathway orchestrating embryonic development, mainly of the CNS and limbs. In vertebrates, SHH signaling is mediated by the primary cilium, and genetic defects affecting either SHH pathway members or ciliary proteins cause a spectrum of developmental disorders. SUFU is the main negative regulator of the SHH pathway and is essential during development. Indeed, Sufu knock-out is lethal in mice, and recessive pathogenic variants of this gene have never been reported in humans. Through whole-exome sequencing in subjects with Joubert syndrome, we identified four children from two unrelated families carrying homozygous missense variants in SUFU. The children presented congenital ataxia and cerebellar vermis hypoplasia with elongated superior cerebellar peduncles (mild ''molar tooth sign''), typical cranio-facial dysmorphisms (hypertelorism, depressed nasal bridge, frontal bossing), and postaxial polydactyly. Two siblings also showed polymicrogyria. Molecular dynamics simulation predicted random movements of the mutated residues, with loss of the native enveloping movement of the binding site around its ligand GLI3. Functional studies on cellular models and fibroblasts showed that both variants significantly reduced SUFU stability and its capacity to bind GLI3 and promote its cleavage into the repressor form GLI3R. In turn, this impaired SUFU-mediated repression of the SHH pathway, as shown by altered expression levels of several target genes. We demonstrate that germline hypomorphic variants of SUFU cause deregulation of SHH signaling, resulting in recessive developmental defects of the CNS and limbs which share features with both SHH-related disorders and ciliopathies.

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“…However, we consider SUFU haploinsufficiency as the most likely cause for this phenotype because SUFU is a negative regulator of hedgehog signaling. 19,20 Genetic variants in this signaling pathway, including in SHH (OMIM no. 142945) and GLI2 (OMIM no.…”

Section: Submicroscopic Cnvsmentioning

confidence: 99%

A prospective study of the clinical utility of prenatal chromosomal microarray analysis in fetuses with ultrasound abnormalities and an exploration of a framework for reporting unclassified variants and risk factors

Brady

Chiaie

Christenhusz

et al. 2014

Genetics in Medicine

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Original research article INTRODUCTIONConventional karyotyping has been considered the gold standard for routine prenatal genetic diagnosis for many decades now, allowing for microscopic visualization and inspection of chromosomes and thus detection of numerical and structural chromosomal rearrangements. The main limitations are the resolution achieved by G-banding, which is limited to 5-10 Mb at best, and the requirement for cultured cells, needing a minimum of 8-10 days. The introduction of targeted methods of analysis such as fluorescence in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA) overcome the time constraints and resolution limitations inherent to karyotyping but do not provide a genome-wide analysis.1 More recently, molecular karyotyping using genomic microarrays has reached mainstream use in the postnatal diagnostic setting, providing a genome-wide screen for genomic imbalances at a far superior resolution to karyotyping.2 A number of studies have demonstrated the feasibility of prenatal diagnosis by genomic arrays using a variety of platforms, 3-7 but challenges remain in applying high-resolution genomic arrays to prenatal diagnosis. 6,8,9 One of the major ethical issues often raised is how to deal with variants of uncertain significance (VOUS) or risk loci, the detection of which leads to additional challenges for genetic counseling of parents. Furthermore, array analysis may reveal an imbalance for known "risk loci" where the future penetrance is uncertain or may be associated with variable expression. The penetrance risks for a number of recurrent copy-number variations (CNVs) have been estimated based on the frequencies in patients and controls. [10][11][12] However, although it is possible to calculate a populationbased risk, it is impossible in the prenatal setting to predict the phenotypic outcome in the child. Purpose:To evaluate the clinical utility of chromosomal microarrays for prenatal diagnosis by a prospective study of fetuses with abnormalities detected on ultrasound. Methods: Patients referred for prenatal diagnosis due to ultrasound anomalies underwent analysis by array comparative genomic hybridization as the first-tier diagnostic test.Results: A total of 383 prenatal samples underwent analysis by array comparative genomic hybridization. Array analysis revealed causal imbalances in a total of 9.6% of patients (n = 37). Submicroscopic copy-number variations were detected in 2.6% of patients (n = 10/37), and arrays added valuable information over conventional karyotyping in 3.9% of patients (n = 15/37). We highlight a novel advantage of arrays; a 500-kb paternal insertional translocation is the likely driver of a de novo unbalanced translocation, thus improving recurrence risk calculation in this family. Variants of uncertain significance were revealed in 1.6% of patients (n = 6/383). Conclusion:We demonstrate the added value of chromosomal microarrays for prenatal diagnosis in the presence of ultrasound anomalies. We advocate reporting back on...

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Suppressor of Fused Controls Mid-Hindbrain Patterning and Cerebellar Morphogenesis via GLI3 Repressor

Cited by 37 publications

References 35 publications

Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis

Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis

Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranio-facial and Skeletal Defects

A prospective study of the clinical utility of prenatal chromosomal microarray analysis in fetuses with ultrasound abnormalities and an exploration of a framework for reporting unclassified variants and risk factors

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