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1.
Nat Genet ; 37(4): 373-81, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15735646

RESUMO

Autosomal dominant mutations in the gene encoding the basic helix-loop-helix transcription factor Twist1 are associated with limb and craniofacial defects in humans with Saethre-Chotzen syndrome. The molecular mechanism underlying these phenotypes is poorly understood. We show that ectopic expression of the related basic helix-loop-helix factor Hand2 phenocopies Twist1 loss of function in the limb and that the two factors have a gene dosage-dependent antagonistic interaction. Dimerization partner choice by Twist1 and Hand2 can be modulated by protein kinase A- and protein phosphatase 2A-regulated phosphorylation of conserved helix I residues. Notably, multiple Twist1 mutations associated with Saethre-Chotzen syndrome alter protein kinase A-mediated phosphorylation of Twist1, suggesting that misregulation of Twist1 dimerization through either stoichiometric or post-translational mechanisms underlies phenotypes of individuals with Saethre-Chotzen syndrome.


Assuntos
Acrocefalossindactilia/metabolismo , Sequências Hélice-Alça-Hélice , Membro Posterior/anormalidades , Proteínas Nucleares/fisiologia , Fatores de Transcrição/fisiologia , Acrocefalossindactilia/genética , Acrocefalossindactilia/patologia , Sequência de Aminoácidos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Embrião de Galinha/virologia , Galinhas , Sequência Conservada , Proteínas Quinases Dependentes de AMP Cíclico/farmacologia , Dimerização , Humanos , Rim/metabolismo , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Mutação/genética , Proteínas Nucleares/genética , Fenótipo , Fosfoproteínas Fosfatases/farmacologia , Fosforilação/efeitos dos fármacos , Proteína Fosfatase 2 , Homologia de Sequência de Aminoácidos , Fatores de Transcrição/genética , Proteína 1 Relacionada a Twist , Proteínas de Peixe-Zebra
2.
PLoS Biol ; 8(8): e1000446, 2010 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-20711475

RESUMO

Topographic neuronal maps arise as a consequence of axon trajectory choice correlated with the localisation of neuronal soma, but the identity of the pathways coordinating these processes is unknown. We addressed this question in the context of the myotopic map formed by limb muscles innervated by spinal lateral motor column (LMC) motor axons where the Eph receptor signals specifying growth cone trajectory are restricted by Foxp1 and Lhx1 transcription factors. We show that the localisation of LMC neuron cell bodies can be dissociated from axon trajectory choice by either the loss or gain of function of the Reelin signalling pathway. The response of LMC motor neurons to Reelin is gated by Foxp1- and Lhx1-mediated regulation of expression of the critical Reelin signalling intermediate Dab1. Together, these observations point to identical transcription factors that control motor axon guidance and soma migration and reveal the molecular hierarchy of myotopic organisation.


Assuntos
Axônios/fisiologia , Moléculas de Adesão Celular Neuronais/metabolismo , Movimento Celular/fisiologia , Proteínas da Matriz Extracelular/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Proteínas de Homeodomínio/metabolismo , Neurônios Motores/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Proteínas Repressoras/metabolismo , Serina Endopeptidases/metabolismo , Transdução de Sinais , Axônios/metabolismo , Moléculas de Adesão Celular Neuronais/genética , Movimento Celular/efeitos dos fármacos , Proteínas da Matriz Extracelular/genética , Extremidades/inervação , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica no Desenvolvimento , Cones de Crescimento/metabolismo , Proteínas de Homeodomínio/genética , Proteínas com Homeodomínio LIM , Neurônios Motores/metabolismo , Proteínas do Tecido Nervoso/genética , Proteína Reelina , Proteínas Repressoras/genética , Serina Endopeptidases/genética , Medula Espinal/metabolismo , Fatores de Transcrição
3.
Proc Natl Acad Sci U S A ; 106(50): 21185-90, 2009 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-19955443

RESUMO

The adrenal cortex is a critical steroidogenic endocrine tissue, generated at least in part from the coelomic epithelium of the urogenital ridge. Neither the intercellular signals that regulate cortical development and maintenance nor the lineage relationships within the adrenal are well defined. We have explored adrenal Shh activity and found that Shh is expressed in relatively undifferentiated steroidogenic cells, which signal to the overlying capsule and subjacent nonsteroidogenic mesenchyme cells that we also find are progenitors of steroidogenic lineages. Shh-expressing cells also generate all steroidogenic cell types, but not nonsteroidogenic ones. Shh mutant adrenals have a thin capsule and small cortex. Our findings both support a novel dual lineage, Shh-independent and Shh-dependent, model of adrenocortical development, and identify distinct populations of adrenocortical progenitor and candidate stem cells.


Assuntos
Córtex Suprarrenal/crescimento & desenvolvimento , Linhagem da Célula , Proteínas Hedgehog/fisiologia , Transdução de Sinais , Células-Tronco/citologia , Esteroides/biossíntese , Córtex Suprarrenal/química , Animais , Diferenciação Celular , Proteínas Hedgehog/análise , Fatores de Transcrição Kruppel-Like/análise , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Proteína GLI1 em Dedos de Zinco
4.
Dev Biol ; 347(1): 133-46, 2010 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-20732316

RESUMO

The basic helix-loop-helix transcription factor Twist1 is essential for normal limb development. Twist1(-/-) embryos die at midgestation. However, studies on early limb buds found that Twist1(-/-) mutant limb mesenchyme has an impaired response to FGF signaling from the apical ectodermal ridge, which disrupts the feedback loop between the mesenchyme and AER, and reduces and shifts anteriorly Shh expression in the zone of polarizing activity. We have combined Twist1 null, hypomorph and conditional alleles to generate a Twist1 allelic series that survives to birth. As Twist1 activity is reduced, limb skeletal defects progress from preaxial polydactyly to girdle reduction combined with hypoplasia, aplasia or mirror symmetry of all limb segments. With reduced Twist1 activity there is striking and progressive upregulation of ectopic Shh expression in the anterior of the limb, combined with an anterior shift in the posterior Shh domain, which is expressed at normal intensity, and loss of the posterior AER. Consequently limb outgrowth is initially impaired, before an ectopic anterior Shh domain expands the AER, promoting additional growth and repatterning. Reducing the dosage of FGF targets of the Etv gene family, which are known repressors of Shh expression in anterior limb mesenchyme, strongly enhances the anterior skeletal phenotype. Conversely this and other phenotypes are suppressed by reducing the dosage of the Twist1 antagonist Hand2. Our data support a model whereby multiple Twist1 activity thresholds contribute to early limb bud patterning, and suggest how particular combinations of skeletal defects result from differing amounts of Twist1 activity.


Assuntos
Extremidades/embriologia , Proteínas Nucleares/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Cartilagem/embriologia , Cartilagem/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Dosagem de Genes/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/metabolismo , Botões de Extremidades/embriologia , Botões de Extremidades/metabolismo , Camundongos , Modelos Genéticos , Mutação/genética , Proteínas Nucleares/genética , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Proteína 1 Relacionada a Twist/genética
5.
Neuroscience ; 450: 29-47, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33038447

RESUMO

Precise control of limb muscles, and ultimately of limb movement, requires accurate motor innervation. Motor innervation of the vertebrate limb is established by sequential selection of trajectories at successive decision points. Motor axons of the lateral motor column (LMC) segregate at the base of the limb into two groups that execute a choice between dorsal and ventral tissue: medial LMC axons innervate the ventral limb, whereas lateral LMC axons innervate the dorsal limb. We investigated how LMC axons are targeted to the limb using the chick mutant limbless (ll), which has a dorsal transformation of the ventral limb mesenchyme. In ll the spatial pattern of motor projections to the limb is abnormal while their targeting is normal. While extensive, the dorsal transformation of the ll ventral limb mesenchyme is incomplete whereas the generation, specification and targeting of spinal motor neurons are apparently unaffected. Thus, the dorsal-ventral motor axon segregation is an active choice that is independent of the ratio between dorsal and ventral tissue but dependent on the presence of both tissues. Therefore, the fidelity of the motor projections to the limb depends on the presence of both dorsal and ventral compartments, while the geometry of motor projections is controlled by the position of limb dorsal-ventral compartment boundary.


Assuntos
Extremidades , Neurônios Motores , Animais , Axônios , Galinhas , Medula Espinal
6.
Dev Cell ; 26(5): 469-482, 2013 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-23993789

RESUMO

The urothelium is a multilayered epithelium that serves as a barrier between the urinary tract and blood, preventing the exchange of water and toxic substances. It consists of superficial cells specialized for synthesis and transport of uroplakins that assemble into a tough apical plaque, one or more layers of intermediate cells, and keratin 5-expressing basal cells (K5-BCs), which are considered to be progenitors in the urothelium and other specialized epithelia. Fate mapping, however, reveals that intermediate cells rather than K5-BCs are progenitors in the adult regenerating urothelium, that P cells, a transient population, are progenitors in the embryo, and that retinoids are critical in P cells and intermediate cells, respectively, for their specification during development and regeneration. These observations have important implications for tissue engineering and repair and, ultimately, may lead to treatments that prevent loss of the urothelial barrier, a major cause of voiding dysfunction and bladder pain syndrome.


Assuntos
Queratina-5/biossíntese , Células-Tronco/citologia , Sistema Urinário/metabolismo , Uroplaquinas/biossíntese , Urotélio/crescimento & desenvolvimento , Animais , Transporte Biológico/genética , Diferenciação Celular/genética , Epitélio/crescimento & desenvolvimento , Epitélio/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos , Regeneração/genética , Sistema Urinário/citologia , Sistema Urinário/crescimento & desenvolvimento , Uroplaquinas/metabolismo , Urotélio/citologia , Cicatrização
7.
Mol Cell Endocrinol ; 351(1): 19-27, 2012 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-22020162

RESUMO

It has been speculated for a number of years that Sonic hedgehog (Shh) signaling plays an important role in adrenal development. Over the past two years several reports have described the expression and function of Shh pathway genes in the adrenal cortex, using primarily mouse models. The key findings are that Shh signals produced by a population of partially differentiated cortical cells located in the outer cortex/zona glomerulosa are received by non-cortical mesenchymal cells located predominantly in the overlying capsule. This signal is required for growth of both the capsule and the cortex, but not for cortical zonation or steroidogenic cell differentiation. Using molecular genetic tools to define the adrenocortical cell lineages that are descended from both Shh signaling and receiving cells, both capsule and cortical cells were found to have properties of adrenocortical stem and/or progenitor cells. Here we place these observations within the context of prior studies on adrenal development, postnatal adrenal maintenance and adrenocortical stem/progenitor cell lineages.


Assuntos
Linhagem da Célula/fisiologia , Proteínas Hedgehog/metabolismo , Transdução de Sinais/fisiologia , Células-Tronco/metabolismo , Zona Glomerulosa/embriologia , Animais , Humanos , Camundongos , Células-Tronco/citologia , Zona Glomerulosa/citologia , Zona Glomerulosa/crescimento & desenvolvimento
8.
Mol Cell Endocrinol ; 336(1-2): 133-40, 2011 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-21256921

RESUMO

Interpretation of adrenal cortex phenotypes is greatly facilitated by simultaneous examination of multiple markers at single cell resolution. However, the availability of multiple appropriate antibodies can be rate limiting, while their cognate antigens are often subject to variable accessibility. Specific markers not subject to these constraints thus have obvious utility. Here we report that endogenous biotin, when detected in fixed, frozen tissue sections using fluorescent streptavidin, is a specific marker of apparently all cells with steroidogenic potential in the murine adrenal cortex. While streptavidin stains presteroidogenic and mature cortical cells, it does not label the adrenal capsule, medulla or vascular endothelium. Developmental profiles reveal adrenal endogenous biotin labeling from E13.5 through adulthood. Comparisons with zonal markers, hypothalamic-pituitary-adrenal (HPA) axis-remodeled tissue, transgenic Shh-nLacZ or Gli1-nLacZ animals, and Shh mutant embryos further demonstrate the utility of this approach. Fluorescent streptavidin applied using a simple one-step staining protocol thus provides a potent counterstain for use in adrenal analyses.


Assuntos
Córtex Suprarrenal/citologia , Córtex Suprarrenal/metabolismo , Biotina/metabolismo , Esteroides/biossíntese , Córtex Suprarrenal/crescimento & desenvolvimento , Animais , Animais Recém-Nascidos , Biomarcadores/metabolismo , Crioultramicrotomia , Proteínas Hedgehog/metabolismo , Camundongos , Transdução de Sinais , Coloração e Rotulagem , Estreptavidina/metabolismo , Fatores de Tempo , Fixação de Tecidos
9.
Mol Cell Endocrinol ; 336(1-2): 117-22, 2011 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-21094676

RESUMO

Sonic hedgehog signaling was recently demonstrated to play an important role in murine adrenal cortex development. The organization of the rat adrenal differs from that of the mouse, with the zona glomerulosa and zona fasciculata separated by an undifferentiated zone in the rat, but not in the mouse. In the present study we aimed to determine the mRNA expression patterns of Sonic hedgehog and the hedgehog signaling pathway components Patched-1 and Gli1 in the developing and adult rat adrenal. Sonic hedgehog expression was detected at the periphery of the cortex in cells lacking CYP11B1 and CYP11B2 expression, while signal-receiving cells were localized in the overlying capsule mesenchyme. Using combined in situ hybridization and immunohistochemistry we found that the cells expressing Sonic hedgehog lie between the CYP11B2 and CYP11B1 layers, and thus Sonic hedgehog expression defines one cell population of the undifferentiated zone.


Assuntos
Córtex Suprarrenal/citologia , Córtex Suprarrenal/embriologia , Envelhecimento/metabolismo , Proteínas Hedgehog/metabolismo , Córtex Suprarrenal/metabolismo , Animais , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/genética , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos , Receptores Patched , Receptor Patched-1 , Transporte Proteico , Ratos , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Proteína GLI1 em Dedos de Zinco
10.
PLoS One ; 4(4): e5173, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19352514

RESUMO

The inhibitory or negative Smads, Smad6 and Smad7, block TGFbeta superfamily signals of both the BMP and TGFbeta classes by antagonizing the intracellular signal transduction machinery. We report the cloning of one Smad6 and two Smad7 (Smad7a and Smad7b) chick homologs and their expression and regulation in the developing limb. Smad6 and Smad7a are expressed in dynamic patterns reflecting the domains of BMP gene expression in the limb. Activation and inhibition of the BMP signaling pathway in limb mesenchyme indicates that negative Smad gene expression is regulated, at least in part, by BMP family signals.


Assuntos
Extremidades/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Proteína Smad6/genética , Proteína Smad7/genética , Sequência de Aminoácidos , Animais , Proteínas Morfogenéticas Ósseas/genética , Embrião de Galinha , Clonagem Molecular , Dados de Sequência Molecular , Filogenia , Proteína Smad6/química , Proteína Smad7/química
11.
J Endocrinol ; 198(3): 439-50, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18524957

RESUMO

The hedgehog (Hh) pathway is an evolutionarily conserved signalling pathway that is required for many essential tissue and cellular properties such as patterning fields of cells or regulating cell differentiation and proliferation. Disruption of the pathway results in serious pathologies. In this review, we provide an update on recent findings in the field of vertebrate Hh signalling and also describe contributions of Hh signalling to the development, maintenance and pathology of endocrine tissues.


Assuntos
Sistema Endócrino/metabolismo , Sistema Endócrino/patologia , Proteínas Hedgehog/fisiologia , Transdução de Sinais/fisiologia , Animais , Sistema Endócrino/crescimento & desenvolvimento , Humanos , Modelos Biológicos
12.
Neuron ; 60(6): 1039-53, 2008 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-19109910

RESUMO

Studies of the innervation of limb muscles by spinal motor neurons have helped to define mechanisms by which axons establish trajectories to their targets. Related motor axons select dorsal or ventral pathways at the base of the limb, raising the question of how these alternate trajectories are specified. EphA signaling has been proposed to control the dorsal trajectory of motor axons in conjunction with other signaling systems, although the respective contributions of each system to motor axon guidance are unclear. We show that the expression of EphB receptors by motor axons, and ephrin-B ligands by limb mesenchymal cells, directs the ventral trajectory of motor axons. Our findings reveal symmetry in the molecular strategies that establish this aspect of nerve-muscle connectivity. The involvement of ephrin:Eph signaling in guiding both sets of motor axons raises the possibility that other signaling systems function primarily to refine or modulate a core Eph signaling program.


Assuntos
Axônios/fisiologia , Padronização Corporal/genética , Efrinas/metabolismo , Extremidades/inervação , Neurônios Motores/citologia , Transdução de Sinais/fisiologia , Animais , Embrião de Galinha , Eletroporação/métodos , Embrião de Mamíferos , Efrinas/deficiência , Efrinas/genética , Extremidades/embriologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Proteínas de Fluorescência Verde/genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Peroxidase do Rábano Silvestre/metabolismo , Proteínas com Homeodomínio LIM , Camundongos , Camundongos Knockout , Modelos Biológicos , Mutação/fisiologia , Proteínas de Neurofilamentos/genética , Proteínas de Neurofilamentos/metabolismo , RNA Mensageiro/metabolismo , Receptores da Família Eph/metabolismo , Medula Espinal/citologia , Medula Espinal/embriologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
13.
Neural Dev ; 2: 13, 2007 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-17605791

RESUMO

BACKGROUND: Neuronal topographic map formation requires appropriate selection of axonal trajectories at intermediate choice points prior to target innervation. Axons of neurons in the spinal cord lateral motor column (LMC), as defined by a transcription factor code, are thought to innervate limb target tissues exclusively. Axons of the medial and lateral LMC divisions appear to execute a binary decision at the base of the limb as they choose between ventral and dorsal limb trajectories. The cellular logic that guides motor axon trajectory choices into non-limb tissues such as the ventral flank remains unclear. RESULTS: We determined the spinal cord motor column origin of motor nerves that innervate ventral flank tissues at hindlimb level. We found unexpectedly that a subset of medial LMC axons innervates ventral non-limb mesenchyme at hindlimb level, rather than entering ventral limb mesenchyme. We also found that in a conditional BmprIa mutant where all ventral hindlimb mesenchyme is converted to a dorsal identity, all medial LMC axons are redirected into the ventral flank, while lateral LMC axons innervate the bidorsal limb. CONCLUSION: We have found that medial LMC neurons innervate both ventral flank and limb targets. While normally only a subset of medial LMC axons innervate the flank, all are capable of doing so. Furthermore, LMC axons execute a ternary, rather than binary, choice at the base of the limb between ventral flank, ventral limb and dorsal limb trajectories. When making this choice, medial and lateral LMC axons exhibit different and asymmetric relative preferences for these three trajectories. These data redefine the LMC as a motor column that innervates both limb and body tissues.


Assuntos
Axônios/fisiologia , Padronização Corporal/genética , Extremidades/embriologia , Extremidades/inervação , Neurônios Motores/fisiologia , Medula Espinal/embriologia , Animais , Axônios/ultraestrutura , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/genética , Diferenciação Celular/genética , Efrinas/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Cones de Crescimento/fisiologia , Cones de Crescimento/ultraestrutura , Proteínas de Homeodomínio/genética , Fatores de Transcrição Kruppel-Like/genética , Proteínas com Homeodomínio LIM , Mesoderma/citologia , Mesoderma/fisiologia , Camundongos , Camundongos Knockout , Neurônios Motores/citologia , Músculo Esquelético/inervação , Músculo Esquelético/fisiologia , Plasticidade Neuronal/genética , Proteína com Dedos de Zinco da Leucemia Promielocítica , Receptores da Família Eph/genética , Medula Espinal/citologia , Fatores de Transcrição/genética
14.
Dev Biol ; 262(1): 94-106, 2003 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-14512021

RESUMO

Limb growth in higher vertebrate embryos is initially due to the outgrowth of limb buds and later continues as a result of elongation of the skeletal elements. The distal limb mesenchyme is crucial for limb bud outgrowth. Members of the Hairy/Enhancer of Split family of DNA binding transcriptional repressors can be effectors of Notch signaling and often act to maintain cell populations in an undifferentiated, proliferating state, properties predicted for the distal limb mesenchyme. We find that a member of this family, c-hairy1, is expressed in this region and that two alternatively spliced isoforms, c-hairy1A and c-hairy1B, of this gene are produced, predicting proteins that differ in their basic, DNA binding, domains. Viral misexpression of c-hairy1A causes a reduction in size of the limb and shortened skeletal elements, without affecting the chondrocyte differentiation program. Misexpression of c-hairy1B leads to a significantly lesser shortening of the bones, implying functional differences between the two isoforms. We conclude that c-hairy1 regulates the size of the limb, suggesting a role for Notch signaling in the distal mesenchyme.


Assuntos
Proteínas Aviárias , Botões de Extremidades/crescimento & desenvolvimento , Proteínas/fisiologia , Processamento Alternativo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Desenvolvimento Ósseo , Embrião de Galinha , Proteínas de Membrana/fisiologia , Proteínas/genética , Receptores Notch
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