RESUMO
Formins are highly conserved proteins that have essential roles in remodelling the actin and microtubule cytoskeletons to influence eukaryotic cell shape and behaviour. Recent work has identified numerous cellular factors that locally recruit, activate or inactivate formins to bridle and unleash their potent effects on actin nucleation and elongation. The effects of formins on microtubules have also begun to be described, which places formins in a prime position to coordinate actin and microtubule dynamics. The emerging complexity in the mechanisms governing formins mirrors the wide range of essential functions that they perform in cell motility, cell division and cell and tissue morphogenesis.
Assuntos
Actinas/metabolismo , Citoesqueleto/metabolismo , Proteínas Fetais/metabolismo , Proteínas dos Microfilamentos/metabolismo , Microtúbulos/metabolismo , Proteínas Nucleares/metabolismo , Actinas/química , Animais , Citoesqueleto/química , Forminas , Humanos , Microtúbulos/químicaRESUMO
A fundamental problem in developmental neuroscience is understanding how extracellular cues link to complex intracellular signaling pathways to drive stage-specific developmental decisions. During the formation of the mammalian peripheral nervous system, bone morphogenetic proteins (BMPs) promote neuronal differentiation. BMPs also maintain the expression of early glial genes such as GFAP, while blocking the acquisition of a mature, myelinating Schwann cell phenotype. We investigated the BMP-activated signaling pathways that contribute to early glial gene expression to address the question of how specific signaling interactions contribute to cell fate decisions in neural crest lineages. Using a neural-crest-derived cell line that exhibits the characteristics of immature Schwann cells, we found that BMP2 promotes GFAP expression using Smad signaling as well as the phosphoinositide-3 kinase (PI3K) and mitogen-activated protein kinase1/2extracellular signal-regulated kinase- (MEK1/2/ERK) pathways. The GFAP promoter does not contain known Smad consensus sites, suggesting that Smads may act indirectly to promote GFAP expression. We provide evidence that this indirect effect may be mediated via induction of immediate early genes and the transcription factor Sp1 by demonstrating that these transcriptional regulators are induced by BMP2 and contribute to GFAP promoter activity. These findings demonstrate new roles for intracellular kinase pathways in mediating the effects of BMPs during the early stages of glial differentiation and suggest that differential contributions by signaling and transcriptional networks may contribute to the range of effects of BMPs on neuronal and glial development during the formation of the peripheral nervous system.
Assuntos
Astrócitos/metabolismo , Proteína Morfogenética Óssea 2/metabolismo , Expressão Gênica/genética , Proteína Glial Fibrilar Ácida/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Análise de Variância , Animais , Astrócitos/efeitos dos fármacos , Western Blotting , Proteína Morfogenética Óssea 2/farmacologia , Butadienos/farmacologia , Linhagem Celular , Células Cultivadas , Cromonas/farmacologia , Inibidores Enzimáticos/farmacologia , Expressão Gênica/efeitos dos fármacos , Genes Precoces/genética , Proteína Glial Fibrilar Ácida/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Morfolinas/farmacologia , Nitrilas/farmacologia , Compostos Orgânicos/farmacologia , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fatores de Tempo , TransfecçãoRESUMO
Cells require actin nucleators to catalyze the de novo assembly of filaments and actin elongation factors to control the rate and extent of polymerization. Nucleation and elongation factors identified to date include Arp2/3 complex, formins, Ena/VASP, and newcomers Spire, Cobl, and Lmod. Here, we discuss recent advances in understanding their activities and mechanisms and new evidence for their cooperation and interaction in vivo. Earlier models had suggested that different nucleators function independently to assemble distinct actin arrays. However, more recent observations indicate that the construction of most cellular actin networks depends on the activities of multiple actin assembly-promoting factors working in concert.