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1.
Dev Cell ; 57(15): 1817-1832.e5, 2022 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-35835116

RESUMO

Stochastic mechanisms diversify cell fates during development. How cells randomly choose between two or more fates remains poorly understood. In the Drosophila eye, the random mosaic of two R7 photoreceptor subtypes is determined by expression of the transcription factor Spineless (Ss). We investigated how cis-regulatory elements and trans factors regulate nascent transcriptional activity and chromatin compaction at the ss gene locus during R7 development. The ss locus is in a compact state in undifferentiated cells. An early enhancer drives transcription in all R7 precursors, and the locus opens. In differentiating cells, transcription ceases and the ss locus stochastically remains open or compacts. In SsON R7s, ss is open and competent for activation by a late enhancer, whereas in SsOFF R7s, ss is compact, and repression prevents expression. Our results suggest that a temporally dynamic antagonism, in which transcription drives large-scale decompaction and then compaction represses transcription, controls stochastic fate specification.


Assuntos
Proteínas de Drosophila , Células Fotorreceptoras de Invertebrados , Animais , Cromatina/genética , Cromatina/metabolismo , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Células Fotorreceptoras de Invertebrados/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
2.
Neuron ; 87(4): 751-63, 2015 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-26291159

RESUMO

In commissural neurons of Drosophila, the conserved Frazzled (Fra)/Deleted in Colorectal Cancer (DCC) receptor promotes midline axon crossing by signaling locally in response to Netrin and by inducing transcription of commissureless (comm), an antagonist of Slit-Roundabout midline repulsion, through an unknown mechanism. Here, we show that Fra is cleaved to release its intracellular domain (ICD), which shuttles between the cytoplasm and the nucleus, where it functions as a transcriptional activator. Rescue and gain-of-function experiments demonstrate that the Fra ICD is sufficient to regulate comm expression and that both γ-secretase proteolysis of Fra and Fra's function as a transcriptional activator are required for its ability to regulate comm in vivo. Our data uncover an unexpected role for the Fra ICD as a transcription factor whose activity regulates the responsiveness of commissural axons at the midline and raise the possibility that nuclear signaling may be a common output of axon guidance receptors.


Assuntos
Axônios/fisiologia , Líquido Intracelular/fisiologia , Receptores de Superfície Celular/fisiologia , Fatores de Transcrição/fisiologia , Animais , Animais Geneticamente Modificados , Axônios/química , Drosophila , Proteínas de Drosophila/análise , Proteínas de Drosophila/fisiologia , Receptores de Netrina , Receptores de Superfície Celular/análise
3.
Wiley Interdiscip Rev Dev Biol ; 4(4): 377-89, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25779002

RESUMO

In bilaterally symmetric animals, the precise assembly of neural circuitry at the midline is essential for coordination of the left and right sides of the body. Commissural axons must first be directed across the midline and then be prevented from re-crossing in order to ensure proper midline connectivity. Here, we review the attractants and repellents that direct axonal navigation at the ventral midline and the receptors on commissural neurons through which they signal. In addition, we discuss the mechanisms that commissural axons use to switch their responsiveness to midline-derived cues, so that they are initially responsive to midline attractants and subsequently responsive to midline repellents.


Assuntos
Padronização Corporal/fisiologia , Movimento Celular/fisiologia , Interneurônios Comissurais/fisiologia , Sinais (Psicologia) , Drosophila/embriologia , Modelos Neurológicos , Morfogênese/fisiologia , Animais , Axônios/fisiologia , Polaridade Celular/fisiologia , Camundongos
4.
Cell ; 151(4): 778-793, 2012 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-23141537

RESUMO

It is not understood how Hsp104, a hexameric AAA+ ATPase from yeast, disaggregates diverse structures, including stress-induced aggregates, prions, and α-synuclein conformers connected to Parkinson disease. Here, we establish that Hsp104 hexamers adapt different mechanisms of intersubunit collaboration to disaggregate stress-induced aggregates versus amyloid. To resolve disordered aggregates, Hsp104 subunits collaborate noncooperatively via probabilistic substrate binding and ATP hydrolysis. To disaggregate amyloid, several subunits cooperatively engage substrate and hydrolyze ATP. Importantly, Hsp104 variants with impaired intersubunit communication dissolve disordered aggregates, but not amyloid. Unexpectedly, prokaryotic ClpB subunits collaborate differently than Hsp104 and couple probabilistic substrate binding to cooperative ATP hydrolysis, which enhances disordered aggregate dissolution but sensitizes ClpB to inhibition and diminishes amyloid disaggregation. Finally, we establish that Hsp104 hexamers deploy more subunits to disaggregate Sup35 prion strains with more stable "cross-ß" cores. Thus, operational plasticity enables Hsp104 to robustly dissolve amyloid and nonamyloid clients, which impose distinct mechanical demands.


Assuntos
Amiloide/metabolismo , Proteínas de Choque Térmico/química , Proteínas de Choque Térmico/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Endopeptidase Clp , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Humanos , Doença de Parkinson/metabolismo , Príons/metabolismo , Dobramento de Proteína
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