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1.
Nature ; 618(7965): 543-549, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37225983

RESUMO

The development of paired appendages was a key innovation during evolution and facilitated the aquatic to terrestrial transition of vertebrates. Largely derived from the lateral plate mesoderm (LPM), one hypothesis for the evolution of paired fins invokes derivation from unpaired median fins via a pair of lateral fin folds located between pectoral and pelvic fin territories1. Whilst unpaired and paired fins exhibit similar structural and molecular characteristics, no definitive evidence exists for paired lateral fin folds in larvae or adults of any extant or extinct species. As unpaired fin core components are regarded as exclusively derived from paraxial mesoderm, any transition presumes both co-option of a fin developmental programme to the LPM and bilateral duplication2. Here, we identify that the larval zebrafish unpaired pre-anal fin fold (PAFF) is derived from the LPM and thus may represent a developmental intermediate between median and paired fins. We trace the contribution of LPM to the PAFF in both cyclostomes and gnathostomes, supporting the notion that this is an ancient trait of vertebrates. Finally, we observe that the PAFF can be bifurcated by increasing bone morphogenetic protein signalling, generating LPM-derived paired fin folds. Our work provides evidence that lateral fin folds may have existed as embryonic anlage for elaboration to paired fins.


Assuntos
Nadadeiras de Animais , Evolução Biológica , Mesoderma , Peixe-Zebra , Animais , Nadadeiras de Animais/anatomia & histologia , Nadadeiras de Animais/embriologia , Nadadeiras de Animais/crescimento & desenvolvimento , Larva/anatomia & histologia , Larva/crescimento & desenvolvimento , Mesoderma/anatomia & histologia , Mesoderma/embriologia , Mesoderma/crescimento & desenvolvimento , Peixe-Zebra/anatomia & histologia , Peixe-Zebra/embriologia , Peixe-Zebra/crescimento & desenvolvimento , Proteínas Morfogenéticas Ósseas/metabolismo
2.
Development ; 137(3): 389-94, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20081187

RESUMO

Although the regulation of osteoblast and adipocyte differentiation from mesenchymal stem cells has been studied for some time, very little is known about what regulates their appearance in discrete regions of the embryo. Here we show that, as in other vertebrates, zebrafish osteoblasts and adipocytes originate in part from cephalic neural crest (CNC) precursors. We investigated the roles that the retinoic acid (RA) and Peroxisome proliferator-activated receptor gamma (Pparg) pathways play in vivo and found that both pathways act on CNC to direct adipocyte differentiation at the expense of osteoblast formation. In addition, we identify two distinct roles for RA in the osteoblast lineage: an early role in blocking the recruitment of osteoblasts and a later role in mature osteoblasts to promote bone matrix synthesis. These findings might help to increase our understanding of skeletal and obesity-related diseases and aid in the development of stem cell-based regenerative therapies.


Assuntos
Crista Neural/citologia , PPAR gama/fisiologia , Tretinoína/fisiologia , Adipócitos/citologia , Animais , Matriz Óssea/crescimento & desenvolvimento , Diferenciação Celular , Linhagem da Célula , Osteoblastos/citologia , Células-Tronco/citologia , Peixe-Zebra
3.
PLoS Genet ; 4(7): e1000136, 2008 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-18654627

RESUMO

Mutations in human Exostosin genes (EXTs) confer a disease called Hereditary Multiple Exostoses (HME) that affects 1 in 50,000 among the general population. Patients with HME have a short stature and develop osteochondromas during childhood. Here we show that two zebrafish mutants, dackel (dak) and pinscher (pic), have cartilage defects that strongly resemble those seen in HME patients. We have previously determined that dak encodes zebrafish Ext2. Positional cloning of pic reveals that it encodes a sulphate transporter required for sulphation of glycans (Papst1). We show that although both dak and pic are required during cartilage morphogenesis, they are dispensable for chondrocyte and perichondral cell differentiation. They are also required for hypertrophic chondrocyte differentiation and osteoblast differentiation. Transplantation analysis indicates that dak(-/-) cells are usually rescued by neighbouring wild-type chondrocytes. In contrast, pic(-/-) chondrocytes always act autonomously and can disrupt the morphology of neighbouring wild-type cells. These findings lead to the development of a new model to explain the aetiology of HME.


Assuntos
Proteínas de Transporte de Ânions/genética , Regulação da Expressão Gênica no Desenvolvimento , N-Acetilglucosaminiltransferases/genética , Osteogênese/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento , Animais , Proteínas de Transporte de Ânions/fisiologia , Clonagem Molecular , Embrião não Mamífero , Marcadores Genéticos , Homozigoto , Perda de Heterozigosidade , Repetições de Microssatélites , Modelos Animais , Mutação , N-Acetilglucosaminiltransferases/fisiologia , Osteogênese/fisiologia , Mapeamento Físico do Cromossomo , RNA Mensageiro/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/fisiologia
4.
Dev Dyn ; 239(6): 1901-4, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20503385

RESUMO

On October 29, 2009, researchers and physicians gathered at the Sheraton Four Points Hotel in Boston for 4 days to discuss a disease called multiple hereditary exostoses (MHE). MHE is an autosomal dominant disease that is associated with mutations in two enzymes that are required for heparan sulfate (HS) synthesis. Children with the disease form numerous benign bone tumors (osteochondromas) and have >2% chance of developing chondrosarcoma. The aim of the meeting was to generate new ideas for the diagnoses, treatment, and cure of this disease. Discussions ranged from orthopedic surgical treatment and patients' personal experiences to fundamental questions in skeletal biology and the precise molecular role that HS plays in developmental signaling pathways.


Assuntos
Osso e Ossos/patologia , Exostose Múltipla Hereditária/genética , Exostose Múltipla Hereditária/cirurgia , Neoplasias Ósseas/genética , Neoplasias Ósseas/cirurgia , Boston , Carboidratos/genética , Criança , Condrossarcoma/genética , Exostose Múltipla Hereditária/patologia , Heparitina Sulfato/genética , Humanos , Mutação , Osteocondroma/genética
5.
Dis Model Mech ; 12(9)2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31383797

RESUMO

Reduced bone quality or mineral density predict susceptibility to fracture and also attenuate subsequent repair. Bone regrowth is also compromised by bacterial infection, which exacerbates fracture site inflammation. Because of the cellular complexity of fracture repair, as well as genetic and environmental influences, there is a need for models that permit visualisation of the fracture repair process under clinically relevant conditions. To characterise the process of fracture repair in zebrafish, we employed a crush fracture of fin rays, coupled with histological and transgenic labelling of cellular responses; the results demonstrate a strong similarity to the phased response in humans. We applied our analysis to a zebrafish model of osteogenesis imperfecta (OI), which shows reduced bone quality, spontaneous fractures and propensity for non-unions. We found deficiencies in the formation of a bone callus during fracture repair in our OI model and showed that clinically employed antiresorptive bisphosphonates can reduce spontaneous fractures in OI fish and also measurably reduce fracture callus remodelling in wild-type fish. The csf1ra mutant, which has reduced osteoclast numbers, also showed reduced callus remodelling. Exposure to excessive bisphosphonate, however, disrupted callus repair. Intriguingly, neutrophils initially colonised the fracture site, but were later completely excluded. However, when fractures were infected with Staphylococcus aureus, neutrophils were retained and compromised repair. This work elevates the zebrafish bone fracture model and indicates its utility in assessing conditions of relevance to an orthopaedic setting with medium throughput.This article has an associated First Person interview with the first author of the paper.


Assuntos
Fraturas Ósseas/patologia , Peixe-Zebra/fisiologia , Alendronato/farmacologia , Alendronato/uso terapêutico , Nadadeiras de Animais/patologia , Animais , Calo Ósseo/efeitos dos fármacos , Calo Ósseo/patologia , Difosfonatos/farmacologia , Difosfonatos/uso terapêutico , Modelos Animais de Doenças , Consolidação da Fratura/efeitos dos fármacos , Fraturas Ósseas/tratamento farmacológico , Fraturas Ósseas/microbiologia , Fraturas não Consolidadas/patologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/patologia , Osteogênese Imperfeita/patologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia
6.
J Exp Zool B Mol Dev Evol ; 310(4): 355-69, 2008 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-18338789

RESUMO

Vertebrate head muscles exhibit a highly conserved pattern of innervation and skeletal connectivity and yet it is unclear whether the molecular basis of their development is likewise conserved. Using the highly conserved expression of Engrailed 2 (En2) as a marker of identity in the dorsal mandibular muscles of zebrafish, we have investigated the molecular signals and tissues required for patterning these muscles. We show that muscle En2 expression is not dependent on signals from the adjacent neural tube, pharyngeal endoderm or axial mesoderm and that early identity of head muscles does not require bone morphogenetic pathway, Notch or Hedgehog (Hh) signalling. However, constrictor dorsalis En2 expression is completely lost after a loss of fibroblast growth factor (Fgf) signalling and we show that is true throughout head muscle development. These results suggest that head muscle identity is dependent on Fgf signalling. Data from experiments performed in chick suggest a similar regulation of En2 genes by Fgf signalling revealing a conserved mechanism for specifying head muscle identity. We present evidence that another key gene important in the development of mouse head muscles, Tbx1, is also critical for specification of mandibular arch muscle identity and that this is independent of Fgf signalling. These data imply that dorsal mandibular arch muscle identity in fish, chick and mouse is specified by a highly conserved molecular process despite differing functions of these muscles in different lineages.


Assuntos
Padronização Corporal/fisiologia , Mandíbula/embriologia , Músculo Esquelético/embriologia , Peixe-Zebra/embriologia , Animais , Fatores de Crescimento de Fibroblastos/metabolismo , Proteínas de Homeodomínio/metabolismo , Imuno-Histoquímica , Hibridização In Situ , Mutação/genética , Proteínas do Tecido Nervoso/metabolismo , Transdução de Sinais/fisiologia , Especificidade da Espécie , Peixe-Zebra/genética
7.
PLoS One ; 10(12): e0144982, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26689368

RESUMO

Osteoblast differentiation from mesenchymal cells is regulated by multiple signalling pathways. Here we have analysed the roles of Fibroblast Growth Factor (FGF) and canonical Wingless-type MMTV integration site (Wnt/ß-Catenin) signalling pathways on zebrafish osteogenesis. We have used transgenic and chemical interference approaches to manipulate these pathways and have found that both pathways are required for osteoblast differentiation in vivo. Our analysis of bone markers suggests that these pathways act at the same stage of differentiation to initiate expression of the osteoblast master regulatory gene osterix (osx). We use two independent approaches that suggest that osx is a direct target of these pathways. Firstly, we manipulate signalling and show that osx gene expression responds with similar kinetics to that of known transcriptional targets of the FGF and Wnt pathways. Secondly, we have performed ChIP with transcription factors for both pathways and our data suggest that a genomic region in the first intron of osx mediates transcriptional activation. Based upon these data, we propose that FGF and Wnt/ß-Catenin pathways act in part by directing transcription of osx to promote osteoblast differentiation at sites of bone formation.


Assuntos
Diferenciação Celular/fisiologia , Fatores de Crescimento de Fibroblastos/metabolismo , Osteoblastos/metabolismo , Fatores de Transcrição/biossíntese , Via de Sinalização Wnt/fisiologia , Proteínas de Peixe-Zebra/biossíntese , Peixe-Zebra/metabolismo , beta Catenina/metabolismo , Animais , Fatores de Crescimento de Fibroblastos/genética , Osteoblastos/citologia , Osteogênese/fisiologia , Fator de Transcrição Sp7 , Fatores de Transcrição/genética , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , beta Catenina/genética
8.
PLoS One ; 7(1): e29734, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22253766

RESUMO

Multiple Osteochondromas (MO; previously known as multiple hereditary exostosis) is an autosomal dominant genetic condition that is characterized by the formation of cartilaginous bone tumours (osteochondromas) at multiple sites in the skeleton, secondary bursa formation and impingement of nerves, tendons and vessels, bone curving, and short stature. MO is also known to be associated with arthritis, general pain, scarring and occasional malignant transformation of osteochondroma into secondary peripheral chondrosarcoma. MO patients present additional complains but the relevance of those in relation to the syndromal background needs validation. Mutations in two enzymes that are required during heparan sulphate synthesis (EXT1 or EXT2) are known to cause MO. Previously, we have used zebrafish which harbour mutations in ext2 as a model for MO and shown that ext2⁻/⁻ fish have skeletal defects that resemble those seen in osteochondromas. Here we analyse dental defects present in ext2⁻/⁻ fish. Histological analysis reveals that ext2⁻/⁻ fish have very severe defects associated with the formation and the morphology of teeth. At 5 days post fertilization 100% of ext2⁻/⁻ fish have a single tooth at the end of the 5(th) pharyngeal arch, whereas wild-type fish develop three teeth, located in the middle of the pharyngeal arch. ext2⁻/⁻ teeth have abnormal morphology (they were shorter and thicker than in the WT) and patchy ossification at the tooth base. Deformities such as split crowns and enamel lesions were found in 20% of ext2⁺/⁻ adults. The tooth morphology in ext2⁻/⁻ was partially rescued by FGF8 administered locally (bead implants). Our findings from zebrafish model were validated in a dental survey that was conducted with assistance of the MHE Research Foundation. The presence of the malformed and/or displaced teeth with abnormal enamel was declared by half of the respondents indicating that MO might indeed be also associated with dental problems.


Assuntos
Exostose Múltipla Hereditária/patologia , Proteoglicanas de Heparan Sulfato/deficiência , Doenças Dentárias/patologia , Peixe-Zebra/metabolismo , Adulto , Envelhecimento/patologia , Animais , Biomarcadores/metabolismo , Exostose Múltipla Hereditária/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteoglicanas de Heparan Sulfato/metabolismo , Humanos , Larva , Mutação/genética , N-Acetilglucosaminiltransferases/deficiência , N-Acetilglucosaminiltransferases/metabolismo , Fenótipo , Transdução de Sinais , Dente/crescimento & desenvolvimento , Dente/metabolismo , Dente/patologia , Doenças Dentárias/genética , Peixe-Zebra/genética
9.
Mech Dev ; 128(1-2): 141-52, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21126582

RESUMO

In tetrapod long bones, Hedgehog signalling is required for osteoblast differentiation in the perichondrium. In this work we analyse skeletogenesis in zebrafish larvae treated with the Hedgehog signalling inhibitor cyclopamine. We show that cyclopamine treatment leads to the loss of perichondral ossification of two bones in the head. We find that the Hedgehog co-receptors patched1 and patched2 are expressed in regions of the perichondrium that will form bone before the onset of ossification. We also show that cyclopamine treatment strongly reduces the expression of osteoblast markers in the perichondrium and that perichondral ossification is enhanced in patched1 mutant fish. This data suggests a conserved role for Hedgehog signalling in promoting perichondral osteoblast differentiation during vertebrate skeletal development. However, unlike what is seen during long bone development, we did not observe ectopic chondrocytes in the perichondrium when Hedgehog signalling is blocked. This result may point to subtle differences between the development of the skeleton in the skull and limb.


Assuntos
Diferenciação Celular , Proteínas Hedgehog/metabolismo , Receptores de Superfície Celular/metabolismo , Transdução de Sinais , Peixe-Zebra/metabolismo , Animais , Biomarcadores/metabolismo , Diferenciação Celular/efeitos dos fármacos , Condrócitos/citologia , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Colágeno Tipo X/metabolismo , Regulação para Baixo/efeitos dos fármacos , Embrião não Mamífero/citologia , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Proteínas Hedgehog/genética , Proteínas de Membrana , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteogênese/efeitos dos fármacos , Receptores Patched , Receptor Patched-1 , Receptores de Superfície Celular/deficiência , Receptores de Superfície Celular/genética , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Alcaloides de Veratrum/farmacologia , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
10.
Eur J Med Chem ; 46(9): 4125-32, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21726921

RESUMO

A series of highly potent indole-3-glyoxylamide based antiprion agents was previously characterized, focusing on optimization of structure-activity relationship (SAR) at positions 1-3 of the indole system. New libraries interrogating the SAR at indole C-4 to C-7 now demonstrate that introducing electron-withdrawing substituents at C-6 may improve biological activity by up to an order of magnitude, and additionally confer higher metabolic stability. For the present screening libraries, both the degree of potency and trends in SAR were consistent across two cell line models of prion disease, and the large majority of compounds showed no evidence of toxic effects in zebrafish. The foregoing observations thus make the indole-3-glyoxylamides an attractive lead series for continuing development as potential therapeutic agents against prion disease.


Assuntos
Indóis/química , Indóis/farmacologia , Microssomos/efeitos dos fármacos , Príons/efeitos dos fármacos , Animais , Linhagem Celular , Descoberta de Drogas , Indóis/efeitos adversos , Relação Estrutura-Atividade , Peixe-Zebra
11.
Dev Dyn ; 238(2): 459-66, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19161246

RESUMO

The transcription factors RUNX2 and OSX have been shown to act sequentially to direct mammalian osteoblast differentiation. RUNX2 is required during the early stages of commitment and acts in part to activate Osx transcription. OSX and RUNX2 then act to direct transcription of bone matrix proteins. Here, we investigate the expression of these genes and others during zebrafish osteoblastogenesis. Using whole-mount in situ hybridization, we find that, during the formation of a given bone, the zebrafish homologues of mouse Runx2 (runx2a and runx2b) are typically expressed before the onset of osx. osx expression is usually followed by up-regulation of the bone matrix proteins, col1a2 and osteonectin. These results suggest that the mammalian pathway is conserved during development of the head and shoulder skeleton of zebrafish. We also analyze the expression of three atypical bone markers (tcf7, cvl2, and col10a1) in an effort to place them within this canonical hierarchy.


Assuntos
Matriz Óssea/metabolismo , Diferenciação Celular/fisiologia , Osteoblastos/citologia , Peixe-Zebra/embriologia , Animais , Biomarcadores/metabolismo , Padronização Corporal , Osteoblastos/metabolismo , Fator de Transcrição Sp7 , Fatores de Transcrição/metabolismo , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismo
12.
Development ; 135(11): 1935-46, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18469222

RESUMO

The Trithorax group (TrxG) is composed of diverse, evolutionary conserved proteins that form chromatin-associated complexes accounting for epigenetic transcriptional memory. However, the molecular mechanisms by which particular loci are marked for reactivation after mitosis are only partially understood. Here, based on genetic analyses in zebrafish, we identify the multidomain protein Brpf1 as a novel TrxG member with a central role during development. brpf1 mutants display anterior transformations of pharyngeal arches due to progressive loss of anterior Hox gene expression. Brpf1 functions in association with the histone acetyltransferase Moz (Myst3), an interaction mediated by the N-terminal domain of Brpf1, and promotes histone acetylation in vivo. Brpf1 recruits Moz to distinct sites of active chromatin and remains at chromosomes during mitosis, mediated by direct histone binding of its bromodomain, which has a preference for acetylated histones, and its PWWP domain, which binds histones independently of their acetylation status. This is the first demonstration of histone binding for PWWP domains. Mutant analyses further show that the PWWP domain is absolutely essential for Brpf1 function in vivo. We conclude that Brpf1, coordinated by its particular set of domains, acts by multiple mechanisms to mediate Moz-dependent histone acetylation and to mark Hox genes for maintained expression throughout vertebrate development.


Assuntos
Proteínas de Transporte/metabolismo , Histonas/metabolismo , Proteínas Nucleares/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Acetilação , Proteínas Adaptadoras de Transdução de Sinal , Animais , Sítios de Ligação/genética , Região Branquial/anatomia & histologia , Região Branquial/crescimento & desenvolvimento , Região Branquial/metabolismo , Proteínas de Transporte/genética , Linhagem Celular , Cromatina/metabolismo , Proteínas de Ligação a DNA , Regulação da Expressão Gênica no Desenvolvimento , Histona Acetiltransferases/genética , Histona Acetiltransferases/metabolismo , Humanos , Imunoprecipitação , Hibridização In Situ , Camundongos , Proteínas Nucleares/genética , Ligação Proteica , Proteínas Recombinantes/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento , Proteínas de Peixe-Zebra/genética
13.
Development ; 131(15): 3681-92, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15229178

RESUMO

The pituitary gland consists of two major parts: the neurohypophysis, which is of neural origin; and the adenohypophysis, which is of non-neural ectodermal origin. Development of the adenohypophysis is governed by signaling proteins from the infundibulum, a ventral structure of the diencephalon that gives rise to the neurohypophysis. In mouse, the fibroblast growth factors Fgf8, Fgf10 and Fgf18 are thought to affect multiple processes of pituitary development: morphogenesis and patterning of the adenohypophyseal anlage; and survival, proliferation and differential specification of adenohypophyseal progenitor cells. Here, we investigate the role of Fgf3 during pituitary development in the zebrafish, analyzing lia/fgf3 null mutants. We show that Fgf3 signaling from the ventral diencephalon is required in a non-cell autonomous fashion to induce the expression of lim3, pit1 and other pituitary-specific genes in the underlying adenohypophyseal progenitor cells. Despite the absence of such early specification steps, fgf3 mutants continue to form a distinct pituitary anlage of normal size and shape, until adenohypophyseal cells die by apoptosis. We further show that Sonic Hedgehog (Shh) cannot rescue pituitary development, although it is able to induce adenohypophyseal cells in ectopic placodal regions of fgf3 mutants, indicating that Fgf3 does not act via Shh, and that Shh can act independently of Fgf3. In sum, our data suggest that Fgf3 signaling primarily promotes the transcriptional activation of genes regulating early specification steps of adenohypophyseal progenitor cells. This early specification seems to be essential for the subsequent survival of pituitary cells, but not for pituitary morphogenesis or pituitary cell proliferation.


Assuntos
Sobrevivência Celular/fisiologia , Diencéfalo/embriologia , Fatores de Crescimento de Fibroblastos/metabolismo , Morfogênese/fisiologia , Adeno-Hipófise/embriologia , Transdução de Sinais/fisiologia , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/embriologia , Sequência de Aminoácidos , Animais , Apoptose , Padronização Corporal , Linhagem da Célula , Diencéfalo/metabolismo , Estruturas Embrionárias/anormalidades , Estruturas Embrionárias/anatomia & histologia , Fator 10 de Crescimento de Fibroblastos , Fator 3 de Crescimento de Fibroblastos , Fatores de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog , Humanos , Hibridização In Situ , Camundongos , Dados de Sequência Molecular , Adeno-Hipófise/citologia , Alinhamento de Sequência , Transativadores/genética , Transativadores/metabolismo , Peixe-Zebra/anormalidades , Peixe-Zebra/anatomia & histologia , Proteínas de Peixe-Zebra/genética
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