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1.
Dev Biol ; 396(2): 214-23, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25446536

RESUMO

During limb development Pax3 positive myoblasts delaminate from the hypaxial dermomyotome of limb level somites and migrate into the limb bud where they form the dorsal and ventral muscle masses. Only then do they begin to differentiate and express markers of myogenic commitment and determination such as Myf5 and MyoD. However the signals regulating this process remain poorly characterised. We show that FGF18, which is expressed in the distal mesenchyme of the limb bud, induces premature expression of both Myf5 and MyoD and that blocking FGF signalling also inhibits endogenous MyoD expression. This expression is mediated by ERK MAP kinase but not PI3K signalling. We also show that retinoic acid (RA) can inhibit the myogenic activity of FGF18 and that blocking RA signalling allows premature induction of MyoD by FGF18 at HH19. We propose a model where interactions between FGF18 in the distal limb and retinoic acid in the proximal limb regulate the timing of myogenic gene expression during limb bud development.


Assuntos
Diferenciação Celular/fisiologia , Extremidades/embriologia , Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Modelos Biológicos , Mioblastos/fisiologia , Tretinoína/metabolismo , Animais , Embrião de Galinha , Primers do DNA/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Hibridização In Situ , Proteína MyoD/metabolismo , Fator Regulador Miogênico 5/metabolismo , Fosforilação
2.
PLoS One ; 12(12): e0189395, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29206875

RESUMO

[This corrects the article DOI: 10.1371/journal.pone.0185775.].

3.
PLoS One ; 12(10): e0185775, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28972999

RESUMO

Limb muscles derive from pax3 expressing precursor cells that migrate from the hypaxial somite into the developing limb bud. Once there they begin to differentiate and express muscle determination genes such as MyoD. This process is regulated by a combination of inductive or inhibitory signals including Fgf18, retinoic acid, HGF, Notch and IGFs. IGFs are well known to affect late stages of muscle development and to promote both proliferation and differentiation. We examined their roles in early stage limb bud myogenesis using chicken embryos as an experimental model. Grafting beads soaked in purified recombinant IGF-I, IGF-II or small molecule inhibitors of specific signaling pathways into developing chick embryo limbs showed that both IGF-I and IGF-II induce expression of the early stage myogenic markers pax3 and MyoD as well as myogenin. Their effects on pax3 and MyoD expression were blocked by inhibitors of both the IGF type I receptor (picropodophyllotoxin, PPP) and MEK (U0126). The PI3K inhibitor LY294002 blocked IGF-II, but not IGF-I, induction of pax3 mRNA as well as the IGF-I, but not IGF-II, induction of MyoD mRNA. In addition SU5402, an FGFR/ VEGFR inhibitor, blocked the induction of MyoD by both IGFs but had no effect on pax3 induction, suggesting a role for FGF or VEGF signaling in their induction of MyoD. This was confirmed by in situ hybridization showing that FGF18, a known regulator of MyoD in limb myoblasts, was induced by IGF-I. In addition to their well-known effects on later stages of myogenesis via their induction of myogenin expression, both IGF-I and IGF-II induced pax3 and MyoD expression in developing chick embryos, indicating that they also regulate early stages of myogenesis. The data suggests that the IGFs may have slightly different effects on IGF1R signal transduction via PI3K and that their stimulatory effects on MyoD expression may be indirect, possibly via induction of FGF18 expression.


Assuntos
Embrião de Galinha/efeitos dos fármacos , Membro Posterior/efeitos dos fármacos , Fator de Crescimento Insulin-Like II/farmacologia , Fator de Crescimento Insulin-Like I/farmacologia , Desenvolvimento Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Animais , Butadienos/farmacologia , Embrião de Galinha/metabolismo , Cromonas/farmacologia , Inibidores Enzimáticos/farmacologia , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Membro Posterior/metabolismo , Morfolinas/farmacologia , Desenvolvimento Muscular/fisiologia , Músculo Esquelético/metabolismo , Proteína MyoD/genética , Proteína MyoD/metabolismo , Miogenina/genética , Miogenina/metabolismo , Nitrilas/farmacologia , Fator de Transcrição PAX3/genética , Fator de Transcrição PAX3/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Podofilotoxina/análogos & derivados , Podofilotoxina/farmacologia , Pirróis/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
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