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1.
Development ; 147(21)2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32376681

RESUMO

Cilia are complex cellular protrusions consisting of hundreds of proteins. Defects in ciliary structure and function, many of which have not been characterised molecularly, cause ciliopathies: a heterogeneous group of human syndromes. Here, we report on the FOXJ1 target gene Cfap206, orthologues of which so far have only been studied in Chlamydomonas and Tetrahymena In mouse and Xenopus, Cfap206 was co-expressed with and dependent on Foxj1 CFAP206 protein localised to the basal body and to the axoneme of motile cilia. In Xenopus crispant larvae, the ciliary beat frequency of skin multiciliated cells was enhanced and bead transport across the epidermal mucociliary epithelium was reduced. Likewise, Cfap206 knockout mice revealed ciliary phenotypes. Electron tomography of immotile knockout mouse sperm flagella indicated a role in radial spoke formation reminiscent of FAP206 function in Tetrahymena Male infertility, hydrocephalus and impaired mucociliary clearance of the airways in the absence of laterality defects in Cfap206 mutant mice suggests that Cfap206 may represent a candidate for the subgroup of human primary ciliary dyskinesias caused by radial spoke defects.


Assuntos
Encéfalo/embriologia , Encéfalo/metabolismo , Proteínas do Citoesqueleto/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Pulmão/metabolismo , Depuração Mucociliar , Motilidade dos Espermatozoides , Animais , Axonema/metabolismo , Corpos Basais/metabolismo , Cílios/metabolismo , Proteínas do Citoesqueleto/química , Desenvolvimento Embrionário , Células Epiteliais/metabolismo , Fluorescência , Hidrocefalia/patologia , Infertilidade Masculina/patologia , Masculino , Camundongos Knockout , Muco/metabolismo , Mutação/genética , Transporte Proteico , Espermatozoides/metabolismo , Espermatozoides/ultraestrutura , Xenopus laevis/embriologia , Xenopus laevis/metabolismo
2.
Dev Biol ; 459(2): 109-125, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31884020

RESUMO

Malfunctions of motile cilia cause a variety of developmental defects and diseases in humans and animal model organisms. Defects include impaired mucociliary clearance of the airways, sperm immotility, hydrocephalus and organ laterality. Here, we characterize the evolutionary conserved Cfap43 gene by loss-of-function experiments in the mouse and the frog Xenopus laevis. Cfap43 is expressed in tissues carrying motile cilia and acts as a target gene of the transcription factor FOXJ1, which is essential for the induction of motile ciliogenesis. We show that CFAP43, a protein of unknown biochemical function, localizes to the ciliary axoneme. CFAP43 is involved in the regulation of the beating frequency of tracheal cilia and loss of CFAP43 causes severe mucus accumulation in the nasal cavity. Likewise, morphant and crispant frog embryos revealed impaired function of motile cilia of the larval epidermis, a model for airway mucociliary epithelia. CFAP43 participates in the formation of flagellar axonemes during spermatogenesis as mice mutant for Cfap43 display male infertility, consistent with observations in male sterile patients. In addition, mice mutant for Cfap43 display early onset hydrocephalus. Together, these results confirm the role of CFAP43 in the male reproductive tract and pinpoint additional functions in airway epithelia mucus clearance and brain development.


Assuntos
Cílios/metabolismo , Proteínas do Citoesqueleto/metabolismo , Proteínas de Xenopus/metabolismo , Animais , Proteínas do Citoesqueleto/genética , Células Epidérmicas/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Hidrocefalia/genética , Infertilidade Masculina/genética , Masculino , Camundongos , Camundongos Knockout , Cauda do Espermatozoide/metabolismo , Espermatogênese/genética , Espermatozoides/metabolismo , Traqueia/citologia , Proteínas de Xenopus/genética , Xenopus laevis
3.
Development ; 143(24): 4736-4748, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27965440

RESUMO

Motile cilia move extracellular fluids or mediate cellular motility. Their function is essential for embryonic development, adult tissue homeostasis and reproduction throughout vertebrates. FOXJ1 is a key transcription factor for the formation of motile cilia but its downstream genetic programme is only partially understood. Here, we characterise a novel FOXJ1 target, Cfap157, that is specifically expressed in motile ciliated tissues in mouse and Xenopus in a FOXJ1-dependent manner. CFAP157 protein localises to basal bodies and interacts with tubulin and the centrosomal protein CEP350. Cfap157 knockout mice appear normal but homozygous males are infertile. Spermatozoa display impaired motility and a novel phenotype: Cfap157-deficient sperm exhibit axonemal loops, supernumerary axonemal profiles with ectopic accessory structures, excess cytoplasm and clustered mitochondria in the midpiece regions, and defective axonemes along the flagella. Our study thus demonstrates an essential sperm-specific function for CFAP157 and suggests that this novel FOXJ1 effector is part of a mechanism that acts during spermiogenesis to suppress the formation of supernumerary axonemes and ensures a correct ultrastructure.


Assuntos
Axonema/metabolismo , Proteínas do Citoesqueleto/metabolismo , Flagelos/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Motilidade dos Espermatozoides/fisiologia , Espermatogênese/fisiologia , Espermatozoides/metabolismo , Animais , Corpos Basais/metabolismo , Proteínas do Citoesqueleto/genética , Fatores de Transcrição Forkhead/genética , Masculino , Camundongos , Camundongos Knockout , Morfogênese/fisiologia , Espermatozoides/citologia , Transcrição Gênica/genética , Xenopus laevis
4.
Dev Biol ; 430(1): 188-201, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28778799

RESUMO

Development of the central nervous system requires orchestration of morphogenetic processes which drive elevation and apposition of the neural folds and their fusion into a neural tube. The newly formed tube gives rise to the brain in anterior regions and continues to develop into the spinal cord posteriorly. Conspicuous differences between the anterior and posterior neural tube become visible already during neural tube closure (NTC). Planar cell polarity (PCP)-mediated convergent extension (CE) movements are restricted to the posterior neural plate, i.e. hindbrain and spinal cord, where they propagate neural fold apposition. The lack of CE in the anterior neural plate correlates with a much slower mode of neural fold apposition anteriorly. The morphogenetic processes driving anterior NTC have not been addressed in detail. Here, we report a novel role for the breast cancer susceptibility gene and microtubule (MT) binding protein Hmmr (Hyaluronan-mediated motility receptor, RHAMM) in anterior neurulation and forebrain development in Xenopus laevis. Loss of hmmr function resulted in a lack of telencephalic hemisphere separation, arising from defective roof plate formation, which in turn was caused by impaired neural tissue narrowing. hmmr regulated polarization of neural cells, a function which was dependent on the MT binding domains. hmmr cooperated with the core PCP component vangl2 in regulating cell polarity and neural morphogenesis. Disrupted cell polarization and elongation in hmmr and vangl2 morphants prevented radial intercalation (RI), a cell behavior essential for neural morphogenesis. Our results pinpoint a novel role of hmmr in anterior neural development and support the notion that RI is a major driving force for anterior neurulation and forebrain morphogenesis.


Assuntos
Morfogênese , Tubo Neural/embriologia , Tubo Neural/metabolismo , Proteínas de Xenopus/metabolismo , Xenopus laevis/embriologia , Xenopus laevis/metabolismo , Animais , Polaridade Celular/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Microtúbulos/ultraestrutura , Modelos Biológicos , Morfolinos/farmacologia , Tubo Neural/citologia , Tubo Neural/ultraestrutura , Prosencéfalo/embriologia , Prosencéfalo/metabolismo , Ligação Proteica/efeitos dos fármacos , Domínios Proteicos , Proteínas de Xenopus/química
5.
Cells Tissues Organs ; 205(5-6): 303-313, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30092565

RESUMO

The function of normal and defective candidate genes for human genetic diseases, which are rapidly being identified in large numbers by human geneticists and the biomedical community at large, will be best studied in relevant and predictive model organisms that allow high-speed verification, analysis of underlying developmental, cellular and molecular mechanisms, and establishment of disease models to test therapeutic options. We describe and discuss the pros and cons of the frog Xenopus, which has been extensively used to uncover developmental mechanisms in the past, but which is being underutilized as a biomedical model. We argue that Xenopus complements the more commonly used mouse and zebrafish as a time- and cost-efficient animal model to study human disease alleles and mechanisms.


Assuntos
Anormalidades Congênitas/genética , Modelos Animais de Doenças , Doenças Genéticas Inatas/genética , Xenopus laevis/genética , Alelos , Animais , Transtornos da Motilidade Ciliar/embriologia , Transtornos da Motilidade Ciliar/genética , Transtornos da Motilidade Ciliar/fisiopatologia , Ciliopatias/embriologia , Ciliopatias/genética , Ciliopatias/fisiopatologia , Anormalidades Congênitas/embriologia , Anormalidades Congênitas/fisiopatologia , Doenças Genéticas Inatas/embriologia , Doenças Genéticas Inatas/fisiopatologia , Cardiopatias Congênitas/embriologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/fisiopatologia , Humanos , Mutação , Xenopus laevis/embriologia , Xenopus laevis/fisiologia
6.
Genesis ; 52(6): 588-99, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24585437

RESUMO

Vertebrates display asymmetric arrangements of inner organs such as heart and stomach. The Nodal signaling cascade in the left lateral plate mesoderm in all cases directs asymmetric morphogenesis and placement during organogenesis. Mechanisms that lead up to left-asymmetric Nodal induction seem to differ between the vertebrates. Cilia produce a leftward extracellular fluid flow in zebrafish, medaka, mouse, rabbit, and Xenopus embryos during neurulation. In Xenopus, earlier asymmetric cues were described. Some, such as Rab11, apparently act in the zygote. Others were efficiently manipulated in ventral-right cells at the four-cell stage, a lineage presumably independent of the ciliated gastrocoel roof plate (GRP) during neurulation. Here, we show that one- and four-cell manipulations of Rab11 showed equal low efficiencies of left-right disturbances. We also reevaluated the lineage of the GRP. By tracing back future ciliated cells from the gastrula to the four-cell stage, we show that ventral cells contribute to ciliated sensory cells at the border of the GRP. Knockdown of the Nodal inhibitor Coco in the ventral right lineage resulted in embryos with ectopic right-sided Nodal and Pitx2c expression. Together, these experiments support a cilia-based mechanism of symmetry breakage in the frog Xenopus.


Assuntos
Blastômeros/metabolismo , Padronização Corporal/fisiologia , Xenopus/embriologia , Proteínas rab de Ligação ao GTP/genética , Animais , Gástrula/embriologia , Gástrula/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Silenciamento de Genes , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Mesoderma/embriologia , Mesoderma/metabolismo , Proteínas de Xenopus/genética , Proteínas de Xenopus/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo
7.
MicroPubl Biol ; 20232023.
Artigo em Inglês | MEDLINE | ID: mdl-37649557

RESUMO

Histone deacetylases (HDACs) are key posttranslational modulators of the proteome. We show that expression of histone deacetylase 6 ( hdac6 ) is dynamic and appears in a tissue specific manner throughout embryonic development of the frog Xenopus laevis . Interestingly, hdac6 transcripts often associate with ciliated tissues, like the left-right organizer at neurula stage or the pronephros. In the embryonic skin, Hdac6 protein localizes to the cilia base, suggesting a functional link.

8.
Front Endocrinol (Lausanne) ; 14: 1258313, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38152138

RESUMO

Very tall people attract much attention and represent a clinically and genetically heterogenous group of individuals. Identifying the genetic etiology can provide important insights into the molecular mechanisms regulating linear growth. We studied a three-generation pedigree with five isolated (non-syndromic) tall members and one individual with normal stature by whole exome sequencing; the tallest man had a height of 211 cm. Six heterozygous gene variants predicted as damaging were shared among the four genetically related tall individuals and not present in a family member with normal height. To gain insight into the putative role of these candidate genes in bone growth, we assessed the transcriptome of murine growth plate by microarray and RNA Seq. Two (Ift140, Nav2) of the six genes were well-expressed in the growth plate. Nav2 (p-value 1.91E-62) as well as Ift140 (p-value of 2.98E-06) showed significant downregulation of gene expression between the proliferative and hypertrophic zone, suggesting that these genes may be involved in the regulation of chondrocyte proliferation and/or hypertrophic differentiation. IFT140, NAV2 and SCAF11 have also significantly associated with height in GWAS studies. Pathway and network analysis indicated functional connections between IFT140, NAV2 and SCAF11 and previously associated (tall) stature genes. Knockout of the all-trans retinoic acid responsive gene, neuron navigator 2 NAV2, in Xenopus supports its functional role as a growth promotor. Collectively, our data expand the spectrum of genes with a putative role in tall stature phenotypes and, among other genes, highlight NAV2 as an interesting gene to this phenotype.


Assuntos
Estatura , DNA Helicases , Animais , Humanos , Masculino , Camundongos , Desenvolvimento Ósseo , Lâmina de Crescimento , Tretinoína , Estatura/genética , DNA Helicases/genética
9.
Nat Genet ; 54(1): 62-72, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34903892

RESUMO

The vertebrate left-right axis is specified during embryogenesis by a transient organ: the left-right organizer (LRO). Species including fish, amphibians, rodents and humans deploy motile cilia in the LRO to break bilateral symmetry, while reptiles, birds, even-toed mammals and cetaceans are believed to have LROs without motile cilia. We searched for genes whose loss during vertebrate evolution follows this pattern and identified five genes encoding extracellular proteins, including a putative protease with hitherto unknown functions that we named ciliated left-right organizer metallopeptide (CIROP). Here, we show that CIROP is specifically expressed in ciliated LROs. In zebrafish and Xenopus, CIROP is required solely on the left side, downstream of the leftward flow, but upstream of DAND5, the first asymmetrically expressed gene. We further ascertained 21 human patients with loss-of-function CIROP mutations presenting with recessive situs anomalies. Our findings posit the existence of an ancestral genetic module that has twice disappeared during vertebrate evolution but remains essential for distinguishing left from right in humans.


Assuntos
Evolução Biológica , Padronização Corporal , Redes Reguladoras de Genes , Metaloproteases , Animais , Humanos , Padronização Corporal/genética , Padronização Corporal/fisiologia , Cílios/genética , Mutação com Perda de Função , Metaloproteases/genética , Metaloproteases/fisiologia , Proteínas/genética , Proteínas/fisiologia , Vertebrados/genética
10.
Sci Rep ; 11(1): 13333, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172766

RESUMO

Cilia are protrusions of the cell surface and composed of hundreds of proteins many of which are evolutionary and functionally well conserved. In cells assembling motile cilia the expression of numerous ciliary components is under the control of the transcription factor FOXJ1. Here, we analyse the evolutionary conserved FOXJ1 target CFAP161 in Xenopus and mouse. In both species Cfap161 expression correlates with the presence of motile cilia and depends on FOXJ1. Tagged CFAP161 localises to the basal bodies of multiciliated cells of the Xenopus larval epidermis, and in mice CFAP161 protein localises to the axoneme. Surprisingly, disruption of the Cfap161 gene in both species did not lead to motile cilia-related phenotypes, which contrasts with the conserved expression in cells carrying motile cilia and high sequence conservation. In mice mutation of Cfap161 stabilised the mutant mRNA making genetic compensation triggered by mRNA decay unlikely. However, genes related to microtubules and cilia, microtubule motor activity and inner dyneins were dysregulated, which might buffer the Cfap161 mutation.


Assuntos
Cílios/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Proteínas de Xenopus/metabolismo , Xenopus laevis/metabolismo , Animais , Axonema/metabolismo , Corpos Basais/metabolismo , Células Epidérmicas/metabolismo , Epiderme/metabolismo , Feminino , Masculino , Camundongos , Microtúbulos/metabolismo
11.
Curr Opin Genet Dev ; 56: 8-14, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31185381

RESUMO

Animal asymmetries are widespread, from lobster claws to human handedness. Controlled by the left-sided Nodal signaling cascade, asymmetric morphogenesis and placement of vertebrate organs (heart, gut, etc.) are executed during embryogenesis. Fish, amphibians and mammals use a ciliated epithelium to break bilateral symmetry and induce the Nodal cascade. Cilia tilt and polarize to the posterior cell pole, such that clockwise rotation causes a leftward flow at the cell surface. Recent progress in Xenopus showed that mechanical strain drives cilia lengthening and polarization. Studying mutant alleles causing human organ situs defects and following novel EvoDevo approaches, new genes were discovered and functionally characterized in the frog, facilitated by a unique set of experimental tools.


Assuntos
Padronização Corporal/genética , Desenvolvimento Embrionário/genética , Regulação da Expressão Gênica no Desenvolvimento , Xenopus laevis/genética , Animais , Cílios/genética , Cílios/metabolismo , Epitélio/embriologia , Epitélio/metabolismo , Evolução Molecular , Estresse Mecânico , Proteínas de Xenopus/genética , Proteínas de Xenopus/metabolismo , Xenopus laevis/embriologia
12.
Front Physiol ; 10: 134, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30858804

RESUMO

Joubert syndrome (JS) is a congenital autosomal-recessive or-in rare cases-X-linked inherited disease. The diagnostic hallmark of the so-called molar tooth sign describes the morphological manifestation of the mid- and hind-brain in axial brain scans. Affected individuals show delayed development, intellectual disability, ataxia, hyperpnea, sleep apnea, abnormal eye, and tongue movements as well as hypotonia. At the cellular level, JS is associated with the compromised biogenesis of sensory cilia, which identifies JS as a member of the large group of ciliopathies. Here we report on the identification of novel compound heterozygous variants (p.Y503C and p.Q485*) in the centrosomal gene PIBF1 in a patient with JS via trio whole exome sequencing. We have studied the underlying disease mechanism in the frog Xenopus, which offers fast assessment of cilia functions in a number of embryological contexts. Morpholino oligomer (MO) mediated knockdown of the orthologous Xenopus pibf1 gene resulted in defective mucociliary clearance in the larval epidermis, due to reduced cilia numbers and motility on multiciliated cells. To functionally assess patient alleles, mutations were analyzed in the larval skin: the p.Q485* nonsense mutation resulted in a disturbed localization of PIBF1 to the ciliary base. This mutant failed to rescue the ciliation phenotype following knockdown of endogenous pibf1. In contrast, the missense variant p.Y503C resulted in attenuated rescue capacity compared to the wild type allele. Based on these results, we conclude that in the case of this patient, JS is the result of a pathogenic combination of an amorphic and a hypomorphic PIBF1 allele. Our study underscores the versatility of the Xenopus model to study ciliopathies such as JS in a rapid and cost-effective manner, which should render this animal model attractive for future studies of human ciliopathies.

13.
Curr Biol ; 28(7): R301-R304, 2018 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-29614284

RESUMO

Symmetry is appealing, be it in architecture, art or facial expression, where symmetry is a key feature to finding someone attractive or not. Yet, asymmetries are widespread in nature, not as an erroneous deviation from the norm but as a way to adapt to the prevailing environmental conditions at a time. Asymmetries in many cases are actively selected for: they might well have increased the evolutionary fitness of a species. Even many single-celled organisms are built asymmetrically, such as the pear-shaped ciliate Paramecium, which may depend on its asymmetry to navigate towards the oxygen-richer surface of turbid waters, at least based on modeling. Everybody knows the lobster with its asymmetric pair of claws, the large crusher usually on the left and the smaller cutter on the right. Snail shells coil asymmetrically, as do the organs they house. Organ asymmetries are found throughout the animal kingdom, referring to asymmetric positioning, asymmetric morphology or both, with the vertebrate heart being an example for the latter. Functional asymmetries, such as that of the human brain with its localization of the language center in one hemisphere, add to the complexity of organ asymmetries and presumably played a decisive role for sociocultural evolution. The evolutionary origin of organ asymmetries may have been a longer than body length gut, which allows efficient retrieval of nutrients, and the need to stow a long gut in the body cavity in an orderly manner that ensures optimal functioning. Vertebrate organ asymmetries (situs solitus) are quite sophisticated: in humans, the apex of the asymmetrically built heart points to the left; the lung in turn, due to space restrictions, has fewer lobes on the left than on the right side (two versus three in humans), stomach and spleen are found on the left, the liver on the right, and small and large intestine coil in a chiral manner (Figure 1A). In very rare cases (1:10,000), the organ situs is inverted (situs inversus), while heterotaxia refers to another rare situation (about 1:1,000), in which subsets of organs show normal or aberrant positioning or morphology (Figure 1B). Individuals with situs solitus or situs inversus are healthy, whereas heterotaxia presents severe congenital malformations. Many human syndromes are known in which patients suffer from laterality defects, such as Katagener syndrome, in which the organ situs is inverted in one half of patients and males are sterile. Snail shells and vertebrate organs are examples of biased asymmetries with on average only one inversion in every 10,000 cases. Other asymmetries such as the coiling of the tails of piglets occur randomly with a 50:50 distribution. This primer exclusively deals with organ asymmetries in the animal kingdom, specifically with the mechanisms that ensure the development of biased asymmetries during embryogenesis.


Assuntos
Evolução Biológica , Lateralidade Funcional , Morfogênese , Vertebrados/fisiologia , Animais , Vertebrados/anatomia & histologia , Vertebrados/classificação
14.
Dev Cell ; 45(3): 277-279, 2018 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-29738704

RESUMO

Left-right organizers require motile and polarized cilia to break symmetry. In this issue of Developmental Cell, Chien et al. (2018) demonstrate that gastrulation-derived mechanical strain of the precursor tissue orients cilia and is required for cilia lengthening and motility.


Assuntos
Padronização Corporal , Cílios , Gastrulação
15.
Sci Rep ; 8(1): 14678, 2018 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-30279523

RESUMO

The transcription factor FOXJ1 is essential for the formation of motile cilia throughout the animal kingdom. Target genes therefore likely constitute an important part of the motile cilia program. Here, we report on the analysis of one of these targets, Fam183b, in Xenopus and mice. Fam183b encodes a protein with unknown function which is conserved from the green algae Chlamydomonas to humans. Fam183b is expressed in tissues harbouring motile cilia in both mouse and frog embryos. FAM183b protein localises to basal bodies of cilia in mIMCD3 cells and of multiciliated cells of the frog larval epidermis. In addition, FAM183b interacts with NUP93, which also localises to basal bodies. During frog embryogenesis, Fam183b was dispensable for laterality specification and brain development, but required for ciliogenesis and motility of epidermal multiciliated cells and nephrostomes, i.e. the embryonic kidney. Surprisingly, mice homozygous for a null allele did not display any defects indicative of disrupted motile ciliary function. The lack of a cilia phenotype in mouse and the limited requirements in frog contrast with high sequence conservation and the correlation of gene expression with the presence of motile cilia. This finding may be explained through compensatory mechanisms at sites where no defects were observed in our FAM183b-loss-of-function studies.


Assuntos
Cílios/fisiologia , Proteínas do Citoesqueleto/metabolismo , Células Epidérmicas/fisiologia , Locomoção , Animais , Corpos Basais/química , Proteínas do Citoesqueleto/genética , Fatores de Transcrição Forkhead/metabolismo , Técnicas de Inativação de Genes , Camundongos , Camundongos Knockout , Xenopus , Proteínas de Xenopus/metabolismo
16.
Curr Biol ; 28(5): 810-816.e3, 2018 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-29478852

RESUMO

Anatomical and functional asymmetries are widespread in the animal kingdom [1, 2]. In vertebrates, many visceral organs are asymmetrically placed [3]. In snails, shells and inner organs coil asymmetrically, and in Drosophila, genitalia and hindgut undergo a chiral rotation during development. The evolutionary origin of these asymmetries remains an open question [1]. Nodal signaling is widely used [4], and many, but not all, vertebrates use cilia for symmetry breaking [5]. In Drosophila, which lacks both cilia and Nodal, the unconventional myosin ID (myo1d) gene controls dextral rotation of chiral organs [6, 7]. Here, we studied the role of myo1d in left-right (LR) axis formation in Xenopus. Morpholino oligomer-mediated myo1d downregulation affected organ placement in >50% of morphant tadpoles. Induction of the left-asymmetric Nodal cascade was aberrant in >70% of cases. Expression of the flow-target gene dand5 was compromised, as was flow itself, due to shorter, fewer, and non-polarized cilia at the LR organizer. Additional phenotypes pinpointed Wnt/planar cell polarity signaling and suggested that myo1d, like in Drosophila [8], acted in the context of the planar cell polarity pathway. Indeed, convergent extension of gastrula explant cultures was inhibited in myo1d morphants, and the ATF2 reporter gene for non-canonical Wnt signaling was downregulated. Finally, genetic interference experiments demonstrated a functional interaction between the core planar cell polarity signaling gene vangl2 and myo1d in LR axis formation. Thus, our data identified myo1d as a common denominator of arthropod and chordate asymmetry, in agreement with a monophyletic origin of animal asymmetry.


Assuntos
Padronização Corporal/genética , Embrião não Mamífero/embriologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Morfogênese/genética , Miosinas/genética , Proteínas de Xenopus/genética , Xenopus laevis/embriologia , Animais , Polaridade Celular/genética , Gástrula/embriologia , Miosinas/metabolismo , Proteínas de Xenopus/metabolismo
17.
J Cardiovasc Dev Dis ; 5(1)2017 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-29367579

RESUMO

Laterality of inner organs is a wide-spread characteristic of vertebrates and beyond. It is ultimately controlled by the left-asymmetric activation of the Nodal signaling cascade in the lateral plate mesoderm of the neurula stage embryo, which results from a cilia-driven leftward flow of extracellular fluids at the left-right organizer. This scenario is widely accepted for laterality determination in wildtype specimens. Deviations from this norm come in different flavors. At the level of organ morphogenesis, laterality may be inverted (situs inversus) or non-concordant with respect to the main body axis (situs ambiguus or heterotaxia). At the level of Nodal cascade gene activation, expression may be inverted, bilaterally induced, or absent. In a given genetic situation, patterns may be randomized or predominantly lacking laterality (absence or bilateral activation). We propose that the distributions of patterns observed may be indicative of the underlying molecular defects, with randomizations being primarily caused by defects in the flow-generating ciliary set-up, and symmetrical patterns being the result of impaired flow sensing, on the left, the right, or both sides. This prediction, the reasoning of which is detailed in this review, pinpoints functions of genes whose role in laterality determination have remained obscure.

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