Lynn McTeir
University of Edinburgh
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Featured researches published by Lynn McTeir.
Bone | 2010
Vicky MacRae; Megan Davey; Lynn McTeir; Sonoko Narisawa; Manisha C. Yadav; José Luis Millán; Colin Farquharson
PHOSPHO1 is a bone-specific phosphatase implicated in the initiation of inorganic phosphate generation for matrix mineralization. The control of mineralization is attributed to the actions of tissue-nonspecific alkaline phosphatase (TNAP). However, matrix vesicles (MVs) containing apatite crystals are present in patients with hypophosphatasia as well as TNAP null (Akp2(-/-)) mice. It is therefore likely that other phosphatases work with TNAP to regulate matrix mineralization. Although PHOSPHO1 and TNAP expression is associated with MVs, it is not known if PHOSPHO1 and TNAP are coexpressed during the early stages of limb development. Furthermore, the functional in vivo role of PHOSPHO1 in matrix mineralization has yet to be established. Here, we studied the temporal expression and functional role of PHOSPHO1 within chick limb bud mesenchymal micromass cultures and also in wild-type and talpid(3) chick mutants. These mutants are characterized by defective hedgehog signalling and the absence of endochondral mineralization. The ability of in vitro micromass cultures to differentiate and mineralize their matrix was temporally associated with increased expression of PHOSPHO1 and TNAP. Comparable changes in expression were noted in developing embryonic legs (developmental stages 23-36HH). Micromass cultures treated with lansoprazole, a small-molecule inhibitor of PHOSPHO1 activity, or FGF2, an inhibitor of chondrocyte differentiation, resulted in reduced alizarin red staining (P<0.05). FGF2 treatment also caused a reduction in PHOSPHO1 (P<0.001) and TNAP (P<0.001) expression. Expression analysis by whole-mount RNA in situ hybridization correlated with qPCR micromass data and demonstrated the existence of a tightly regulated pattern of Phospho1 and Tnap expression which precedes mineralization. Treatment of developing embryos for 5 days with lansoprazole completely inhibited mineralization of all leg and wing long bones as assessed by alcian blue/alizarin red staining. Furthermore, long bones of the talpid(3) chick mutant did not express Phospho1 or Tnap whereas flat bones mineralized normally and expressed both phosphatases. In conclusion, this study has disclosed that PHOSPHO1 expression mirrors that of TNAP during embryonic bone development and that PHOSPHO1 contributes to bone mineralization in developing chick long bones.
Developmental Dynamics | 2011
Ian C. Dunn; I. Robert Paton; Allyson K. Clelland; Sujith Sebastian; Edward J. Johnson; Lynn McTeir; Dawn Windsor; Adrian Sherman; Helen Sang; Dave Burt; Cheryll Tickle; Megan Davey
Point mutations in the intronic ZRS region of Lmbr1, a limb specific cis‐regulatory element of Sonic hedgehog (Shh), are associated with polydactyly in humans, cats, and mice. We and others have recently mapped the dominant preaxial polydactyly (Po) locus in Silkie chickens to a single nucleotide polymorphism (SNP) in the ZRS region. Using polymorphisms in the chicken Shh sequence, we confirm that the ZRS region directly regulates Shh expression in the developing limb causing ectopic Shh expression in the anterior leg, prolonged Shh expression in the posterior limb, and allelic imbalance between wt and Slk Shh alleles in heterozygote limbs. Using Silkie legs, we have explored the consequences of increased Shh expression in the posterior leg on the patterning of the toes, and the induction of preaxial polydactyly. Developmental Dynamics 240:1163–1172, 2011.
eLife | 2015
Louise Stephen; Hasan Tawamie; Gemma M. Davis; Lars Tebbe; Peter Nürnberg; Gudrun Nürnberg; Holger Thiele; Michaela Thoenes; Eugen Boltshauser; Steffen Uebe; Oliver Rompel; André Reis; Arif B. Ekici; Lynn McTeir; Amy M Fraser; Emma A. Hall; Pleasantine Mill; Nicolas Daudet; Courtney E. Cross; Uwe Wolfrum; Rami Abou Jamra; Megan Davey; Hanno J. Bolz
Joubert syndrome (JBTS) is a severe recessive neurodevelopmental ciliopathy which can affect several organ systems. Mutations in known JBTS genes account for approximately half of the cases. By homozygosity mapping and whole-exome sequencing, we identified a novel locus, JBTS23, with a homozygous splice site mutation in KIAA0586 (alias TALPID3), a known lethal ciliopathy locus in model organisms. Truncating KIAA0586 mutations were identified in two additional patients with JBTS. One mutation, c.428delG (p.Arg143Lysfs*4), is unexpectedly common in the general population and may be a major contributor to JBTS. We demonstrate KIAA0586 protein localization at the basal body in human and mouse photoreceptors, as is common for JBTS proteins, and also in pericentriolar locations. We show that loss of TALPID3 (KIAA0586) function in animal models causes abnormal tissue polarity, centrosome length and orientation, and centriolar satellites. We propose that JBTS and other ciliopathies may in part result from cell polarity defects. DOI: http://dx.doi.org/10.7554/eLife.08077.001
Developmental Dynamics | 2013
Louise Stephen; Gemma M. Davis; Katie McTeir; John James; Lynn McTeir; Martin Kierans; Andrew Bain; Megan Davey
Background: Loss of function mutations in the centrosomal protein TALPID3 (KIAA0586) cause a failure of primary cilia formation in animal models and are associated with defective Hedgehog signalling. It is unclear, however, if TALPID3 is required only for primary cilia formation or if it is essential for all ciliogenesis, including that of motile cilia in multiciliate cells. Results: FOXJ1, a key regulator of multiciliate cell fate, is expressed in the dorsal neuroectoderm of the chicken forebrain and hindbrain at stage 20HH, in areas that will give rise to choroid plexuses in both wt and talpid3 embryos. Wt ependymal cells of the prosencephalic choroid plexuses subsequently transition from exhibiting single short cilia to multiple long motile cilia at 29HH (E8). Primary cilia and long motile cilia were only rarely observed on talpid3 ependymal cells. Electron microscopy determined that talpid3 ependymal cells do develop multiple centrosomes in accordance with FOXJ1 expression, but these fail to migrate to the apical surface of ependymal cells although axoneme formation was sometimes observed. Conclusions: TALPID3, which normally localises to the proximal centrosome, is essential for centrosomal migration prior to ciliogenesis but is not directly required for de novo centriologenesis, multiciliated fate, or axoneme formation. Developmental Dynamics 242:923–931, 2013.
Organogenesis | 2014
Megan Davey; Lynn McTeir; Andrew M Barrie; Lucy Freem; Louise Stephen
Sonic hedgehog plays an essential role in maintaining hepatoblasts in a proliferative non-differentiating state during embryogenesis. Transduction of the Hedgehog signaling pathway is dependent on the presence of functional primary cilia and hepatoblasts, therefore, must require primary cilia for normal function. In congenital syndromes in which cilia are absent or non-functional (ciliopathies) hepatorenal fibrocystic disease is common and primarily characterized by ductal plate malformations which underlie the formation of liver cysts, as well as less commonly, by hepatic fibrosis, although a role for abnormal Hedgehog signal transduction has not been implicated in these phenotypes. We have examined liver, lung and rib development in the talpid3 chicken mutant, a ciliopathy model in which abnormal Hedgehog signaling is well characterized. We find that the talpid3 phenotype closely models that of human short-rib polydactyly syndromes which are caused by the loss of cilia, and exhibit hypoplastic lungs and liver failure. Through an analysis of liver and lung development in the talpid3 chicken, we propose that cilia in the liver are essential for the transduction of Hedgehog signaling during hepatic development. The talpid3 chicken represents a useful resource in furthering our understanding of the pathology of ciliopathies beyond the treatment of thoracic insufficiency as well as generating insights into the role Hedgehog signaling in hepatic development.
Current Biology | 2017
Thomas W Marchant; Edward J. Johnson; Lynn McTeir; Craig Johnson; Adam Gow; Tiziana Liuti; Dana Kuehn; Karen L Svenson; Mairead Lesley Bermingham; Michaela Drögemüller; Marc Nussbaumer; Megan Davey; David Argyle; Roger Powell; Sérgio Guilherme; Johann Lang; Gert Ter Haar; Tosso Leeb; Tobias Schwarz; Richard Mellanby; Dylan N. Clements; Jeffrey J. Schoenebeck
Summary In morphological terms, “form” is used to describe an object’s shape and size. In dogs, facial form is stunningly diverse. Facial retrusion, the proximodistal shortening of the snout and widening of the hard palate is common to brachycephalic dogs and is a welfare concern, as the incidence of respiratory distress and ocular trauma observed in this class of dogs is highly correlated with their skull form. Progress to identify the molecular underpinnings of facial retrusion is limited to association of a missense mutation in BMP3 among small brachycephalic dogs. Here, we used morphometrics of skull isosurfaces derived from 374 pedigree and mixed-breed dogs to dissect the genetics of skull form. Through deconvolution of facial forms, we identified quantitative trait loci that are responsible for canine facial shapes and sizes. Our novel insights include recognition that the FGF4 retrogene insertion, previously associated with appendicular chondrodysplasia, also reduces neurocranium size. Focusing on facial shape, we resolved a quantitative trait locus on canine chromosome 1 to a 188-kb critical interval that encompasses SMOC2. An intronic, transposable element within SMOC2 promotes the utilization of cryptic splice sites, causing its incorporation into transcripts, and drastically reduces SMOC2 gene expression in brachycephalic dogs. SMOC2 disruption affects the facial skeleton in a dose-dependent manner. The size effects of the associated SMOC2 haplotype are profound, accounting for 36% of facial length variation in the dogs we tested. Our data bring new focus to SMOC2 by highlighting its clinical implications in both human and veterinary medicine.
Genesis | 2014
Louise Stephen; Edward J. Johnson; Gemma M. Davis; Lynn McTeir; Jamie Pinkham; Neema Jaberi; Megan Davey
Motile cilia are an essential component of the mouse, zebrafish, and Xenopus laevis Left Right Organizers, generating nodal flow and allowing the reception and transduction of mechanosensory signals. Nonmotile primary cilia are also an important component of the Left Right Organizers chemosensory mechanism. It has been proposed in the chicken that signaling in Hensens node, the Left Right Organizer of the chicken, is independent of cilia, based on a lack of evidence of motile cilia or nodal flow. It is speculated that the talpid3 chicken mutant, which has normal left–right patterning despite lacking cilia at many stages of development, is proof of this hypothesis. Here, we examine the evidence for cilia in Hensens node and find that although cilia are present; they are likely to be immotile and incapable of generating nodal flow. Furthermore, we find that early planar cell polarity patterning and ciliogenesis is normal in early talpid3 chicken embryos. We conclude that patterning and development of the early talpid3 chicken is normal, but not necessarily independent of cilia. Although it appears that Hensens node does not require motile cilia or the generation of motile flow, there may remain a requirement for cilia in the transduction of SHH signaling. genesis 52:600–613, 2014.
Human Mutation | 2017
Joe Rainger; Kathleen A. Williamson; Dinesh C. Soares; Julia Truch; Dominic Kurian; Gabriele Gillessen-Kaesbach; Anne Seawright; James Prendergast; Mihail Halachev; Ann P. Wheeler; Lynn McTeir; Andrew C. Gill; Veronica van Heyningen; Megan Davey; David Fitzpatrick
Ocular coloboma (OC) is a defect in optic fissure closure and is a common cause of severe congenital visual impairment. Bilateral OC is primarily genetically determined and shows marked locus heterogeneity. Whole‐exome sequencing (WES) was used to analyze 12 trios (child affected with OC and both unaffected parents). This identified de novo mutations in 10 different genes in eight probands. Three of these genes encoded proteins associated with actin cytoskeleton dynamics: ACTG1, TWF1, and LCP1. Proband‐only WES identified a second unrelated individual with isolated OC carrying the same ACTG1 allele, encoding p.(Pro70Leu). Both individuals have normal neurodevelopment with no extra‐ocular signs of Baraitser–Winter syndrome. We found this mutant protein to be incapable of incorporation into F‐actin. The LCP1 and TWF1 variants each resulted in only minor disturbance of actin interactions, and no further plausibly causative variants were identified in these genes on resequencing 380 unrelated individuals with OC.
Mechanisms of Development | 2018
Violeta Trejo-Reveles; Lynn McTeir; Kim Summers; Joe Rainger
Precise anterior segment (AS) development in the vertebrate eye is essential for maintaining ocular health throughout life. Disruptions to genetic programs can lead to severe structural AS disorders at birth, while more subtle AS defects may disrupt the drainage of ocular fluids and cause dysregulation of intraocular pressure homeostasis, leading to progressive vision loss. To date, the mouse has served as the major model to study AS development and pathogenesis. Here we present an accurate histological atlas of chick AS formation throughout eye development, with a focus on the formation of drainage structures. We performed expression analyses for a panel of known AS disorder genes, and showed that chick PAX6 was localized to cells of neural retina and surface ectoderm derived structures, displaying remarkable similarity to the mouse. We provide a comparison to mouse and humans for chick AS developmental sequences and structures and confirm that AS development shares common features in all three species, although the main AS structures in the chick are developed prior to hatching. These features enable the unique experimental advantages inherent to chick embryos, and we therefore propose the chick as an appropriate additional model for AS development and disease.
Mechanisms of Development | 2009
Jamie Pinkham; Lynn McTeir; Megan Davey
Comparison between related species is a successful approach to uncover conserved and divergent principles of development. Here we studied the pattern of epithalamic asymmetry in zebrafish and medaka, two related teleost species with 115–200 million-year of independent evolution. We found that these species share a strikingly conserved overall pattern of asymmetry in the parapineal–habenular–interpeduncular system. Nodal signalling precedes the left-sided asymmetric positioning and connectivity of the parapineal organ, the enlargement of neuropil in the left habenula compared to the right habenula and the segregation of left–right habenular efferents along the dorsoventral axis of the interpeduncular nucleus. Despite the overall conservation of asymmetry, we observed heterotopic changes in the topology of parapineal efferent connectivity, heterochronic shifts in the timing of developmental events underlying the establishment of asymmetry, and divergent degrees of canalisation of embryo laterality. We are currently testing hypotheses of inter-species variation that link the topology of parapineal efferent connectivity to the underlying organisation of domains within the left habenula, and are also expanding our developmental time comparison to a broader ontogenic context. Together, these findings highlight the usefulness of zebrafish and medaka as comparative tools to study the developmental mechanisms of epithalamic asymmetry in vertebrates.