286 research outputs found
The Meckel-Gruber syndrome protein TMEM67 controls basal body positioning and epithelial branching morphogenesis in mice via the non-canonical Wnt pathway.
No full textCiliopathies are a group of developmental disorders that manifest with multi-organ anomalies. Mutations in TMEM67 (MKS3) cause a range of human ciliopathies, including Meckel-Gruber and Joubert syndromes. In this study we describe multi-organ developmental abnormalities in the Tmem67(tm1Dgen/H1) knockout mouse that closely resemble those seen in Wnt5a and Ror2 knockout mice. These include pulmonary hypoplasia, ventricular septal defects, shortening of the body longitudinal axis, limb abnormalities, and cochlear hair cell stereociliary bundle orientation and basal body/kinocilium positioning defects. The basal body/kinocilium complex was often uncoupled from the hair bundle, suggesting aberrant basal body migration, although planar cell polarity and apical planar asymmetry in the organ of Corti were normal. TMEM67 (meckelin) is essential for phosphorylation of the non-canonical Wnt receptor ROR2 (receptor-tyrosine-kinase-like orphan receptor 2) upon stimulation with Wnt5a-conditioned medium. ROR2 also colocalises and interacts with TMEM67 at the ciliary transition zone. Additionally, the extracellular N-terminal domain of TMEM67 preferentially binds to Wnt5a in an in vitro binding assay. Cultured lungs of Tmem67 mutant mice failed to respond to stimulation of epithelial branching morphogenesis by Wnt5a. Wnt5a also inhibited both the Shh and canonical Wnt/β-catenin signalling pathways in wild-type embryonic lung. Pulmonary hypoplasia phenotypes, including loss of correct epithelial branching morphogenesis and cell polarity, were rescued by stimulating the non-canonical Wnt pathway downstream of the Wnt5a-TMEM67-ROR2 axis by activating RhoA. We propose that TMEM67 is a receptor that has a main role in non-canonical Wnt signalling, mediated by Wnt5a and ROR2, and normally represses Shh signalling. Downstream therapeutic targeting of the Wnt5a-TMEM67-ROR2 axis might, therefore, reduce or prevent pulmonary hypoplasia in ciliopathies and other congenital conditions
Aberrant Wnt signalling and cellular over-proliferation in a novel mouse model of Meckel–Gruber syndrome
No full textAbstractMeckel–Gruber syndrome (MKS) is an embryonic lethal ciliopathy resulting from mutations in genes encoding proteins localising to the primary cilium. Mutations in the basal body protein MKS1 account for 7% of cases of MKS. The condition affects the development of multiple organs, including brain, kidney and skeleton. Here we present a novel Mks1tm1a(EUCOMM)Wtsi knockout mouse which accurately recapitulates the human condition, consistently developing pre-axial polydactyly, complex posterior fossa defects (including the Dandy–Walker malformation), and renal cystic dysplasia. TOPFlash Wnt reporter assays in mouse embryonic fibroblasts (MEFs) showed general de-regulated high levels of canonical Wnt/β-catenin signalling in Mks1−/− cells. In addition to these signalling defects, we also observed ectopic high proliferation in the brain and kidney of mutant animals at mid- to late-gestation. The specific role of Mks1 in regulating cell proliferation was confirmed in Mks1 siRNA knockdown experiments which showed increased levels of proliferation after knockdown, an effect not seen after knockdown of other ciliopathy genes. We suggest that this is a result of the de-regulation of multiple signalling pathways (Wnt, mTOR and Hh) in the absence of functional Mks1. This novel model system offers insights into the role of MKS1 in Wnt signalling and proliferation, and the impact of deregulation of these processes on brain and kidney development in MKS, as well as expanding our understanding of the role of Mks1 in multiple signalling pathways
A snapshot of online wildlife trade: Australian e-commerce trade of native and non-native pets
No full textFunding This project was funded by the Centre for Invasive Species Solutions (Project PO1-I-001). Adam Toomes was additionally supported by the FJ Sandoz PhD Scholarship. Pablo GarcíaDíaz was funded by NERC grants NE/S011641/1 (Newton LATAM programme) and 2022GCBCCONTAIN.Peer reviewe
Scale of unregulated international trade in Australian reptiles and amphibians
No full textReptiles and amphibians are popular in the exotic pet trade, where Australian species are valued for their rarity and uniqueness. Despite a near-complete ban on the export of Australian wildlife, smuggling and subsequent international trade frequently occur in an unregulated and unmonitored manner. In 2022, Australia listed over 100 squamates in Appendix III of the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) to better monitor this trade. We investigated current trade and assessed the value of this Australian CITES listing using web-scraping methods to monitor the online pet trade in Australian reptiles and amphibians, with additional data from published papers, trade databases, and seizure records. Despite the export ban, we identified 170 endemic herpetofauna (reptile and amphibian) species in international trade, 33 of which were not recorded previously in the international market, including 6 newly recorded genera. Ninety-two traded species were included in CITES appendices (59 added in 2022), but at least 78 other traded species remained unregulated. Among these, 5 of the 10 traded threatened species were unlisted, and we recommend they be considered for inclusion in CITES Appendix III. We also recommend the listing of all Diplodactylidae genera in Appendix III. Despite this family representing the greatest number of Australian species in trade, only one genus (of 7 traded) was included in the recent CITES amendments. Overall, a large number of Australian reptile and amphibian species are traded internationally and, although we acknowledge the value of Australia's recent CITES listing, we recommend the consideration of other taxa for similar inclusion in CITES.Sebastian Chekunov, Oliver Stringham, Adam Toomes, Thomas Prowse, Phillip Casse
Variable expressivity of ciliopathy neurological phenotypes that encompass Meckel-Gruber syndrome and Joubert syndrome is caused by complex de-regulated ciliogenesis, Shh and Wnt signalling defects
No full textThe ciliopathies are a group of heterogeneous diseases with considerable variations in phenotype for allelic conditions such as Meckel-Gruber syndrome (MKS) and Joubert syndrome (JBTS) even at the inter-individual level within families. In humans, mutations in TMEM67 (also known as MKS3) cause both MKS and JBTS, with TMEM67 encoding the orphan receptor meckelin (TMEM67) that localizes to the ciliary transition zone. We now describe the Tmem67(tm1(Dgen/H)) knockout mouse model that recapitulates the brain phenotypic variability of these human ciliopathies, with categorization of Tmem67 mutant animals into two phenotypic groups. An MKS-like incipient congenic group (F6 to F10) manifested very variable neurological features (including exencephaly, and frontal/occipital encephalocele) that were associated with the loss of primary cilia, diminished Shh signalling and dorsalization of the caudal neural tube. The 'MKS-like' group also had high de-regulated canonical Wnt/β-catenin signalling associated with hyper-activated Dishevelled-1 (Dvl-1) localized to the basal body. Conversely, a second fully congenic group (F > 10) had less variable features pathognomonic for JBTS (including cerebellar hypoplasia), and retention of abnormal bulbous cilia associated with mild neural tube ventralization. The 'JBTS-like' group had de-regulated low levels of canonical Wnt signalling associated with the loss of Dvl-1 localization to the basal body. Our results suggest that modifier alleles partially determine the variation between MKS and JBTS, implicating the interaction between Dvl-1 and meckelin, or other components of the ciliary transition zone. The Tmem67(tm1(Dgen/H)) line is unique in modelling the variable expressivity of phenotypes in these two ciliopathies
Strengthening protection of endemic wildlife threatened by the international pet trade: The case of the Australian shingleback lizard
No full textFirst published: 05 July 2021Unsustainable wildlife trade threatens an increasing number of species globally. Australia has a particularly rich and endemic herpetofauna, which is coveted on the international pet market. While Australia implements domestic protection of most of its native species, there is little to no regulation of international trade once live animals have been smuggled out of the country. This is a threat for a variety of rare, unique and/or range-restricted species, subspecies and locality morphs. One of these species is the shingleback lizard (Tiliqua rugosa). We compiled Australian seizure data and international online trade data pertaining to shinglebacks. We found all four subspecies in trade across Asia, Europe and North America. Here we provide evidence that all four shingleback subspecies are illegally extracted from the wild in Australia and smuggled to international destinations, where they are sold and distributed globally. While shinglebacks are a protected species in Australia and can only be exported legally under a federal permit, their import into, and trade between, other countries is often not illegal, even in the absence of such a permit. These contradictory legal frameworks apply to the majority of nationally protected native fauna and must be addressed by each importing country on an individual basis; that is, by changing their legislation to cover and protect species that are nationally protected in their native range. Meanwhile, however, we argue that listing T. rugosa in Appendix III of the Convention on International Trade in Endangered Species of Wild Fauna and Flora is a meaningful way to provide other countries with the legal means to confiscate illegally exported shinglebacks from Australia. Our findings and recommendations are directly relevant for potential future Appendix III consideration of other nationally protected species that are found in international trade.S. Heinrich, A. Toomes, C. R. Shepherd, O. C. Stringham, M. Swan, P. Casse
Who's a pretty bird? Predicting the traded abundance of bird species in Australian online pet trade
No full textPublished online: 16 December 2023The increasing popularity of online commerce provides a new opportunity to investigate and quantify the dynamics of pet trade. Understanding these dynamics, including relationships between species characteristics and a species’ relative abundance in trade, can assist in informing trade regulation for conservation and biosecurity. We identified the leading correlates behind the abundance in the Australian pet trade of parrot (Psittaciformes) and passerine (Passeriformes) species. We examined 14,000 online sales of parrots and passerines collected from a popular online Australian marketplace in 2019 (representing 235 species) using an automated data collection method. We identified the characteristics that correlated with online species abundance; including (i) breeding and handling requirements; (ii) trade and availability; and (iii) appearance and behaviour. We found 55% of parrot species and 64% of passerine species traded online were non-native to Australia; of these, 81% and 85% respectively have an extreme risk of establishing invasive populations. Species abundance of both orders was correlated with cheaper prices, which is also associated with a higher invasion risk. Trade in parrots was correlated with attractive birdsongs, being easier to care for, and a preference for native Australian species. Passerine abundance was correlated with attractive plumage colour and, to a lesser extent, the availability of colour mutations and smaller geographic range sizes. These results, combined with an understanding of consumer behaviour and international trends, may help predict which species will become abundant in domestic trade in the future, and identify current and future invasion risks to assist in environmental biosecurity efforts.Katherine G. W. Hill, Oliver C. Stringham, Stephanie Moncayo, Adam Toomes, Jonathan J. Tyler, Phillip Cassey, Steven Delea
results of a pilot trial
No full textLung Cancer still is the major cause of death in malignant diseases. For several years the German Society for Thoracic Surgery attempted to establish an external quality management for the surgical treatment of lung cancer. Despite positive expert opinions and several negotiations no governmental support could be achieved. Therefore a pilot trial was started with financial support from the German Society for Thoracic Surgery and from the Association for Quality Management of Pneumology and Thoracic Surgery. During 2001 data of patients operated for lung cancer were prospectively recorded. Six high volume centres were prepared to participate. Mortality and morbidity rate as well as rate of sleeve resections and mediastinoscopies were selected as quality criteria. For the evaluation percentage and appropriate confidence intervals were used. 1494 interventions in 1099 patients were recorded. The type of resection was lobectomy in 565 (38%) cases, pneumonectomy in 148 (10%) cases and other interventions in 781 (52%) cases. Complications occurred in 31% of lobectomies and pneumonectomies with variations between the hospitals between 20% and 44%. Hospital mortality was 2.8% (1.5-3.5%) for the whole group. For lobectomies the hospital mortality was 2.6%, for pneumonectomies 8.1% (4-33%). The rate of mediastinoscopies in the hospitals varied between 20% and 80%. On the basis of the selected indicator and the quality criteria it could be shown that a quality management is possible.Das Bronchialkarzinom ist nach wie vor die häufigste Todesursache bei malignen Erkrankungen in Deutschland. Seit vielen Jahren versucht die Deutsche Gesellschaft für Thoraxchirurgie eine externe Qualitätssicherungsmaßnahme für die operative Therapie des Bronchialkarzinoms zu initiieren. Trotz vieler Verhandlungen und positiver Begutachtungsergebnisse des Projektes war von den Verantwortlichen im Gesundheitswesen keine öffentliche Förderung zu erhalten. Es wurde daher mit Geldern der Deutschen Gesellschaft für Thoraxchirurgie und des Vereins für Qualitätsmanagement in der Pneumologie und Thoraxchirurgie eine Pilotstudie gestartet. Es wurden Daten von Patienten, die aufgrund eines Bronchialkarzinoms im Jahre 2001 operiert wurden, prospektiv erhoben. Sechs große thoraxchirurgische Kliniken bzw. Abteilungen waren freiwillig bereit teilzunehmen. Qualitätskriterien waren die Letalitäts- und Komplikationsraten sowie die Anzahl der Manschettenresektionen und die Anzahl der Mediastinoskopien pro Haupteingriff. Die Auswertungen erfolgten als Prozentzahlen mit den zugehörigen Konfidenzintervallen. Es wurden 1494 Eingriffe bei 1099 Patienten dokumentiert. Die Eingriffsart war in 565 (38%) Fällen eine Lobektomie, in 148 (10%) Fällen eine Pneumonektomie und in 781 (52%) Fällen andere Eingriffe. Komplikationen traten bei großen Eingriffen bei 31% der Patienten auf. Innerhalb der Kliniken kam es zu Schwankungen zwischen 20% und 44%. Die Krankenhausletalität der gesamten Gruppe betrug 2,8%. Die geringste Letalität betrug 1,5%, die höchste 3,5%. Betrachtet man nur die Patienten, die lobektomiert wurden, so betrug die Letalität der gesamten Gruppe 2,6%. Bei den Pneumonektomien betrug die Letalität 8,1%. Sie schwankte zwischen 4% und 33%. Die Rate der Mediastinoskopien in Bezug auf die kurativen Eingriffe schwankte zwischen 20% und 80%. Anhand des vorgegebenen Indikatorproblems (Bronchialkarzinom) und der Qualitätskriterien konnte in der Studie gezeigt werden, dass eine sinnvolle und aussagekräftige externe Qualitätssicherung in der operativen Thoraxchirurgie mit den erhobenen Daten möglich ist
The ciliary frizzled like receptor Tmem67 regulates canonical Wnt/β-catenin signalling in the developing cerebellum via Hoxb5
No full textPrimary cilia defects result in a group of related pleiotropic malformation syndromes known as ciliopathies, often characterised by cerebellar developmental and foliation defects. Here, we describe the cerebellar anatomical and signalling defects in the Tmem67tm1Dgen/H1 knockout mouse. At mid-gestation, Tmem67 mutant cerebella were hypoplastic and had aberrantly high canonical Wnt/β-catenin signalling, proliferation and apoptosis. Later in development, mutant cerebellar hemispheres had severe foliation defects and inferior lobe malformation, characterized by immature Purkinje cells (PCs). Early postnatal Tmem67 mutant cerebellum had disrupted ciliogenesis and reduced responsiveness to Shh signalling. Transcriptome profiling of Tmem67 mutant cerebella identified ectopic increased expression of homeobox-type transcription factors (Hoxa5, Hoxa4, Hoxb5 and Hoxd3), normally required for early rostral hindbrain patterning. Hoxb5 protein levels were increased in the inferior lobe, and increased canonical Wnt signalling, following loss of TMEM67, was dependent on HOXB5. HOXB5 occupancy at the β-catenin promoter was significantly increased by activation of canonical Wnt signalling in Tmem67-/- mutant cerebellar neurones, suggesting that increased canonical Wnt signalling following mutation or loss of TMEM67 was directly dependent on HOXB5. Our results link dysregulated expression of Hox group genes with ciliary Wnt signalling defects in the developing cerebellum, providing new mechanistic insights into ciliopathy cerebellar hypoplasia phenotypes
- …
