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Query: UMLS:C0038379 (strabismus)
 9,317 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neural tube defects (NTDs) such as spina bifida and anencephaly are common congenital malformations in humans (1/1,000 births) that result from failure of the neural tube to close during embryogenesis. The etiology of NTDs is complex, with both genetic and environmental contributions; the genetic component has been extensively studied with mouse models. Loop-tail (Lp) is a semidominant mutation on mouse chromosome 1 (ref. 4). In the two known Lp alleles (Lp, Lpm1Jus), heterozygous mice exhibit a characteristic looped tail, and homozygous embryos show a completely open neural tube in the hindbrain and spinal region, a condition similar to the severe craniorachischisis defect in humans. Morphological and neural patterning studies indicate a role for the Lp gene product in controlling early morphogenesis and patterning of both axial midline structures and the developing neural plate. The 0.6-cM/0.7-megabase (Mb) Lp interval is delineated proximally by D1Mit113/Apoa2/Fcer1g and distally by Fcer1a/D1Mit149/Spna1 and contains a minimum of 17 transcription units. One of these genes, Ltap, encodes a homolog of Drosophila Strabismus/Van Gogh (Stbm/Vang), a component of the frizzled/dishevelled tissue polarity pathway. Ltap is expressed broadly in the neuroectoderm throughout early neurogenesis and is altered in two independent Lp alleles, identifying this gene as a strong candidate for Lp.
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PMID:Ltap, a mammalian homolog of Drosophila Strabismus/Van Gogh, is altered in the mouse neural tube mutant Loop-tail. 1143 95

We identified two novel mouse mutants with abnormal head-shaking behavior and neural tube defects during the course of independent ENU mutagenesis experiments. The heterozygous and homozygous mutants exhibit defects in the orientation of sensory hair cells in the organ of Corti, indicating a defect in planar cell polarity. The homozygous mutants exhibit severe neural tube defects as a result of failure to initiate neural tube closure. We show that these mutants, spin cycle and crash, carry independent missense mutations within the coding region of Celsr1, encoding a large protocadherin molecule [1]. Celsr1 is one of three mammalian homologs of Drosophila flamingo/starry night, which is essential for the planar cell polarity pathway in Drosophila together with frizzled, dishevelled, prickle, strabismus/van gogh, and rhoA. The identification of mouse mutants of Celsr1 provides the first evidence for the function of the Celsr family in planar cell polarity in mammals and further supports the involvement of a planar cell polarity pathway in vertebrate neurulation.
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PMID:Mutation of Celsr1 disrupts planar polarity of inner ear hair cells and causes severe neural tube defects in the mouse. 1284 12

In addition to the apical-basal polarity pathway operating in epithelial cells, a planar cell polarity (PCP) pathway establishes polarity within the plane of epithelial tissues and is conserved from Drosophila to mammals. In Drosophila, a 'core' group of PCP genes including frizzled (fz), flamingo/starry night, dishevelled (dsh), Van Gogh/strabismus and prickle, function to regulate wing hair, bristle and ommatidial polarity. In vertebrates, the PCP pathway regulates convergent extension movements and neural tube closure, as well as the orientation of stereociliary bundles of sensory hair cells in the inner ear. Here we show that a mutation in the mouse protein tyrosine kinase 7 (PTK7) gene, which encodes an evolutionarily conserved transmembrane protein with tyrosine kinase homology, disrupts neural tube closure and stereociliary bundle orientation, and shows genetic interactions with a mutation in the mouse Van Gogh homologue vangl2. We also show that PTK7 is dynamically localized during hair cell polarization, and that the Xenopus homologue of PTK7 is required for neural convergent extension and neural tube closure. These results identify PTK7 as a novel regulator of PCP in vertebrates.
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PMID:PTK7/CCK-4 is a novel regulator of planar cell polarity in vertebrates. 1522 3

The integument of the Drosophila adult abdomen bears oriented hairs and bristles that indicate the planar polarity of the epidermal cells. We study four polarity genes, frizzled (fz), prickle (pk), Van gogh/strabismus (Vang/stbm) and starry night/flamingo (stan/fmi), and note what happens when these genes are either removed or overexpressed in clones of cells. The edges of the clones are interfaces between cells that carry different amounts of gene products, interfaces that can cause reversals of planar polarity in the clone and wild-type cells outside them. To explain, we present a model that builds on our earlier picture of a gradient of X, the vector of which specifies planar polarity and depends on two cadherin proteins, Dachsous and Fat. We conjecture that the X gradient is read out, cell by cell, as a scalar value of Fz activity, and that Pk acts in this process, possibly to determine the sign of the Fz activity gradient. We discuss evidence that cells can compare their scalar readout of the level of X with that of their neighbours and can set their own readout towards an average of those. This averaging, when it occurs near the edges of clones, changes the scalar response of cells inside and outside the clones, leading to new vectors that change polarity. The results argue that Stan must be present in both cells being compared and acts as a conduit between them for the transfer of information. And also that Vang assists in the receipt of this information. The comparison between neighbours is crucial, because it gives the vector that orients hairs--these point towards the neighbour cell that has the lowest level of Fz activity. Recently, it has been shown that, for a limited period shortly before hair outgrowth in the wing, the four proteins we study, as well as others, become asymmetrically localised in the cell membrane, and this process is thought to be instrumental in the acquisition of cell polarity. However, some results do not fit with this view--we suggest that these localisations may be more a consequence than a cause of planar polarity.
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PMID:Cell interactions and planar polarity in the abdominal epidermis of Drosophila. 1532 45

The "core genes" were identified as a group of genes believed to function as a conserved signaling cassette for the specification of planar polarity in Drosophila Melanogaster, and includes frizzled (fz), van gogh (vang) or strabismus (stbm), prickle (Pk), dishevelled (dsh), flamingo (fmi), and diego. The mutation of each of these genes not only causes the disruption of planar polarity within the wing or the eye of the animal, but also affects the localization of all the other protein members of the core group. These properties emphasize the importance of the interrelations between the proteins of this group. All of these core genes have homologs in vertebrates. Studies in Danio Rerio (zebrafish) and Xenopus laevis (frog) have uncovered other roles for some of these molecules in gastrulation and neurulation, during which the shape of a given tissue will undergo major transformation through cell movements. A disruption in these processes can lead to severe neural tube defects in diverse organisms, including humans. In fact, a large body of evidence suggests that planar polarity proteins are not involved in one specific cascade but in many different ones and many different mechanisms such as, but not limited to, hair or cilia orientation, asymmetric division, cellular movements, or neuronal migration. In mice cochleae, mutations in planar polarity genes lead to defects in the orientation of the stereociliary bundles at the apex of each hair cell. This phenotype established the cochlea as one of the clearest examples of planar polarity in mammals. Although significant progress has been made toward understanding the molecular basis required for the development of planar polarity in invertebrates, similar advances in vertebrates are more recent and rely mainly on the identification of a group of mammalian mutants that affect hair cell stereociliary bundle orientation. These include mutation of vangl2, scrb1, celsr1, PTK-7, dvl1-2, and more recently fz3 and fz6. In this chapter, we describe how to use the mammalian cochlea, which represents one of the best systems to study planar polarity in mammals, to identify planar polarity mutants, study protein distribution, do in vitro analysis, and perform Western blots to analyze putative planar polarity proteins.
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PMID:Detection of planar polarity proteins in mammalian cochlea. 1909 57

Axonal development is a fundamental process for circuit formation in the nervous system and is dependent on many cellular events, including axon initiation, elongation, guidance, and branching. The molecular mechanisms underlying these events have been well studied, especially for axon guidance. In the presence of a guidance cue, the polarization of a growth cone precedes the turning response, which is one example of the diverse forms of cell polarity. Planar cell polarity (PCP) is another example of cell polarity. Although some PCP genes are required for axonal tract formation in vertebrates, it remains elusive whether these genes participate in a common PCP pathway concertedly. Here, we show that essential PCP signaling components, encoded by frizzled (fz), strabismus (stbm), flamingo (fmi), and dishevelled (dsh), are cooperatively required for axonal targeting and branching of the Drosophila mushroom body (MB) neurons. A detailed analysis of these mutants revealed that these components were required for the correct targeting and bifurcation of axons. In addition, we suggest that Wnt5 functions as a ligand in the PCP pathway in this process. Wnt5 mutants showed similar phenotypes to PCP mutants at the single-cell level and genetically interacted with PCP genes. Wnt5 was broadly expressed in the developing brain. We propose that Wnt5 and the PCP pathway concertedly regulate axonal development of the MB.
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PMID:The Wnt5/planar cell polarity pathway regulates axonal development of the Drosophila mushroom body neuron. 2145 Oct 33

Neural tube defects (NTDs) are severe congenital malformations affecting 1-2 in 1,000 live births, whose etiology is multifactorial, involving environmental and genetic factors. NTDs arise as consequence of the failure of fusion of the neural tube early during embryogenesis. NTDs' pathogenesis has been linked to genes involved in folate metabolism, consistent with an epidemiologic evidence that 70% of NTDs can be prevented by maternal periconceptional supplementation. However, polymorphisms in such genes are not linked in all populations, suggesting that other genetic factors and environmental factors could be involved. Animal models have provided crucial mechanistic information and possible candidate genes to explain susceptibility to NTDs. A crucial role has been assigned to the planar cell polarity (PCP) pathway, a highly conserved, non-canonical Wnt-frizzled-dishevelled signaling cascade that plays a key role in establishing and maintaining polarity in the plane of the epithelium and in the process of convergent extension during gastrulation and neurulation in vertebrates. The Loop-tail (Lp) mouse that develops craniorachischisis carry missense mutations in the PCP core gene Vangl2, that is the mammalian homolog of the Drosophila Strabismus/Van gogh (Stbm/Vang). The presence of mutations in human VANGL1 and VANGL2 genes encourages us to extend the investigation to other PCP genes that, with VANGL, play an essential role in neurulation during development.
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PMID:Human neural tube defects: genetic causes and prevention. 2167 47

Branching morphology is a hallmark feature of axons and dendrites and is essential for neuronal connectivity. To understand how this develops, I analyzed the stereotyped pattern of Drosophila mushroom body (MB) neurons, which have single axons branches that extend dorsally and medially. I found that components of the Wnt/Planar Cell Polarity (PCP) pathway control MB axon branching. frizzled mutant animals showed a predominant loss of dorsal branch extension, whereas strabismus (also known as Van Gogh) mutants preferentially lost medial branches. Further results suggest that Frizzled and Strabismus act independently. Nonetheless, branching fates are determined by complex Wnt/PCP interactions, including interactions with Dishevelled and Prickle that function in a context-dependent manner. Branching decisions are MB-autonomous but non-cell-autonomous as mutant and non-mutant neurons regulate these decisions collectively. I found that Wnt/PCP components do not need to be asymmetrically localized to distinct branches to execute branching functions. However, Prickle axonal localization depends on Frizzled and Strabismus.
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PMID:Wnt/PCP proteins regulate stereotyped axon branch extension in Drosophila. 2214 54

This is a report of a 13-month-old boy who presented with a large unilateral fibrovascular stalk and bilateral peripheral retinal avascularity. Although consistent with both persistent fetal vasculature and familial exudative vitreoretinopathy, genetic testing disclosed a novel pathogenic mutation in the frizzled class receptor 4 gene (FZD4, c.427_428delCT). [J Pediatr Ophthalmol Strabismus. 2020;57:e4-e7.].
J Pediatr Ophthalmol Strabismus 2020 Jan 24
PMID:Novel Frizzled-4 Mutation Is Associated With Familial Exudative Vitreoretinopathy Mimicking Persistent Fetal Vasculature. 3197 32