Swaying is a mutant allele of the proto-oncogene Wnt-1

Thomas, Kirk R.; Musci, Teresa S.; Neumann, Paul E.; Capecchi, Mario R.

doi:10.1016/0092-8674(91)90369-a

Cited by 233 publications

(114 citation statements)

References 39 publications

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“…Leptomycin B is able to block the effects of SUFU-wt transfection resulting in high levels of nuclear b-catenin but as expected has no effect on the SUFU-Dex8 transfectants where b-catenin is already nuclear 2002). The importance of WNT signaling is further demonstrated by Wnt-1(À/À) mutant mice that have almost no cerebellum (Thomas et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

Failure of a medulloblastoma-derived mutant of SUFU to suppress WNT signaling

et al. 2004

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Germline mutations of APC in patients with Turcot syndrome (colon cancer and medulloblastoma), was well as somatic mutations of APC, b-catenin, and Axin in sporadic medulloblastomas (MBs) have shown the importance of WNT signaling in the pathogenesis of MB. A subset of children with MB have germline mutations of SUFU, a known inhibitor of Hedgehog signal transduction. A recent report suggested that murine Sufu can bind b-catenin, export it from the nucleus, and thereby repress b-catenin/T-cell factor (Tcf)-mediated transcription. We show that an MB-derived mutant of SUFU has lost the ability to decrease nuclear levels of b-catenin, and cannot inhibit b-catenin/Tcf-mediated transcription as compared to wild type SUFU. Our results suggest that loss of function of SUFU results in overactivity of both the Sonic Hedgehog, and the WNT signaling pathways, leading to excessive proliferation and failure to differentiate resulting in MB.

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Section: Discussionmentioning

confidence: 99%

Failure of a medulloblastoma-derived mutant of SUFU to suppress WNT signaling

et al. 2004

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“…Homozygous or biallelic LRP5 loss of function mutations cause osteoporosis pseudoglioma syndrome [103][104][105] , whereas heterozygous gain of function mutations cause van Buchem disease type 2 (or endosteal hyperostosis) 106 . Wnt1 −/− mice are embryonically lethal and have severe brain abnormalities but no reported skeletal phenotype, whereas the Swaying mouse (which is homozygous for a single nucleotide deletion in Wnt1 in exon 3) survives post natally, has severe osteopenia and a cerebellar defect, similar to some human WNT1 mutations 99,107 .…”

Section: Box 1 | Classification Of Osteogenesis Imperfectamentioning

confidence: 99%

Osteogenesis imperfecta

Marini

Forlino

Bächinger

et al. 2017

Nat Rev Dis Primers

577

582

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| Skeletal deformity and bone fragility are the hallmarks of the brittle bone dysplasia osteogenesis imperfecta. The diagnosis of osteogenesis imperfecta usually depends on family history and clinical presentation characterized by a fracture (or fractures) during the prenatal period, at birth or in early childhood; genetic tests can confirm diagnosis. Osteogenesis imperfecta is caused by dominant autosomal mutations in the type I collagen coding genes (COL1A1 and COL1A2) in about 85% of individuals, affecting collagen quantity or structure. In the past decade, (mostly) recessive, dominant and X-linked defects in a wide variety of genes encoding proteins involved in type I collagen synthesis, processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells have been shown to cause osteogenesis imperfecta. The large number of causative genes has complicated the classic classification of the disease, and although a new genetic classification system is widely used, it is still debated. Phenotypic manifestations in many organs, in addition to bone, are reported, such as abnormalities in the cardiovascular and pulmonary systems, skin fragility, muscle weakness, hearing loss and dentinogenesis imperfecta. Management involves surgical and medical treatment of skeletal abnormalities, and treatment of other complications. More innovative approaches based on gene and cell therapy, and signalling pathway alterations, are under investigation. NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | ARTICLE NUMBER 17052 | 1 PRIMER © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .In this Primer, we provide an overview of epidemio logy, genetics and pathophysiology of osteogenesis imperfecta, as well as diagnosis and management. EpidemiologyStudies from Europe and the United States have found a birth prevalence of osteogenesis imperfecta of 0.3-0.7 per 10,000 births 5,6 . These birth cohort analyses reflect more severe types of osteogenesis imperfecta and do not include more subtle types that become apparent after birth. A population based study that used the Danish National Patient Register found an annual incidence of osteogenesis imperfecta of 1.5 per 10,000 births between 1997 and 2013 (REF. 7). Population surveys in countries with comprehensive medical databases, such as Finland, estimated a prevalence of about 0.5 per 10,000 individ uals 8 , with most having phenotypically milder osteo genesis imperfecta type I and type IV (BOX 1; TABLE 1). Because these birth cohort and population surveys are based on clinical findings and tend to find mutu ally exclusive populations, a reasonable estimate of the incidence of osteogenesis imperfecta is about 1 per 10,000 individuals. Most patients are heterozygous for mutations in COL1A1 or COL1A2. No difference in the prevalence between sexes was reported.Approximately 90% of the 3,000 individuals whose mutations ha...

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“…Indeed, mounting evidence gathered from functional studies of either Wnt ligands or their downstream signaling components, including the complex of receptors, have shown that in the developing brain Wnt signaling participates in patterning the midbrain-hindbrain boundary, which later on gives rise to the brainstem and the cerebellum ( McMahon and Bradley, 1990; Thomas and Capecchi, 1990;Thomas et al, 1991;McMahon et al, 1992;Hall et al, 2000), and forebrain derivatives such as the cerebral cortex, hippocampal formation and the amygdala (Grove et al, 1998;Lako et al, 1998;Lee et al, 2000;Houart et al, 2002;Maretto et al, 2003;Abu-Khalil et al, 2004;Zhou et al, 2004). Remarkably, embryonic transgenic mice expressing active stabilized forms of b-catenin in neuronal precursor cells developed gross enlargements of the cerebral cortex, hippocampus and amygdala Walsh, 2002, 2003).…”

Section: Wnt Signaling and Autismmentioning

confidence: 99%

The ups and downs of Wnt signaling in prevalent neurological disorders

2006

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In order to function properly, the brain must be wired correctly during critical periods in early development. Mistakes in this process are hypothesized to occur in disorders like autism and schizophrenia. Later in life, signaling pathways are essential in maintaining proper communication between neuronal and non-neuronal cells, and disrupting this balance may result in disorders like Alzheimer's disease. The Wnt/b-catenin pathway has a well-established role in cancer. Here, we review recent evidence showing the involvement of Wnt/b-catenin signaling in neurodevelopment as well as in neurodegenerative diseases. We suggest that the onset/development of such pathological conditions may involve the additive effect of genetic variation within Wnt signaling components and of molecules that modulate the activity of this signaling cascade.

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Swaying is a mutant allele of the proto-oncogene Wnt-1

Cited by 233 publications

References 39 publications

Failure of a medulloblastoma-derived mutant of SUFU to suppress WNT signaling

Failure of a medulloblastoma-derived mutant of SUFU to suppress WNT signaling

Osteogenesis imperfecta

The ups and downs of Wnt signaling in prevalent neurological disorders

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