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1.
Development ; 149(5)2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35245348

RESUMO

The hypothalamus displays staggering cellular diversity, chiefly established during embryogenesis by the interplay of several signalling pathways and a battery of transcription factors. However, the contribution of epigenetic cues to hypothalamus development remains unclear. We mutated the polycomb repressor complex 2 gene Eed in the developing mouse hypothalamus, which resulted in the loss of H3K27me3, a fundamental epigenetic repressor mark. This triggered ectopic expression of posteriorly expressed regulators (e.g. Hox homeotic genes), upregulation of cell cycle inhibitors and reduced proliferation. Surprisingly, despite these effects, single cell transcriptomic analysis revealed that most neuronal subtypes were still generated in Eed mutants. However, we observed an increase in glutamatergic/GABAergic double-positive cells, as well as loss/reduction of dopamine, hypocretin and Tac2-Pax6 neurons. These findings indicate that many aspects of the hypothalamic gene regulatory flow can proceed without the key H3K27me3 epigenetic repressor mark, but points to a unique sensitivity of particular neuronal subtypes to a disrupted epigenomic landscape.


Assuntos
Desenvolvimento Embrionário/fisiologia , Hipotálamo/fisiologia , Neurônios/fisiologia , Complexo Repressor Polycomb 2/genética , Proteínas do Grupo Polycomb/genética , Animais , Proliferação de Células/genética , Repressão Epigenética/genética , Feminino , Masculino , Camundongos , Mutação/genética , Transcriptoma/genética
2.
Mol Syst Biol ; 19(5): e11148, 2023 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-36938679

RESUMO

Early-life stress can result in life-long effects that impact adult health and disease risk, but little is known about how such programming is established and maintained. Here, we show that such epigenetic memories can be initiated in the Drosophila embryo before the major wave of zygotic transcription, and higher-order chromatin structures are established. An early short heat shock results in elevated levels of maternal miRNA and reduced levels of a subgroup of zygotic genes in stage 5 embryos. Using a Dicer-1 mutant, we show that the stress-induced decrease in one of these genes, the insulator-binding factor Elba1, is dependent on functional miRNA biogenesis. Reduction in Elba1 correlates with the upregulation of early developmental genes and promotes a sustained weakening of heterochromatin in the adult fly as indicated by an increased expression of the PEV wm4h reporter. We propose that maternal miRNAs, retained in response to an early embryonic heat shock, shape the subsequent de novo heterochromatin establishment that occurs during early development via direct or indirect regulation of some of the earliest expressed genes, including Elba1.


Assuntos
Proteínas de Drosophila , MicroRNAs , Animais , Drosophila/genética , Drosophila/metabolismo , Heterocromatina/genética , Heterocromatina/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Embrião não Mamífero/metabolismo , Desenvolvimento Embrionário/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Drosophila melanogaster/metabolismo
3.
Development ; 146(6)2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30837222

RESUMO

The nervous system displays a daunting cellular diversity. Neuronal subtypes differ from each other in several aspects, including their neurotransmitter expression and axon projection. These aspects can converge, but can also diverge, such that neurons expressing the same neurotransmitter may project axons to different targets. It is not well understood how regulatory programs converge/diverge to associate/dissociate different cell fate features. Studies of the Drosophila Tv1 neurons have identified a regulatory cascade, ladybird early→collier→apterous/eyes absent→dimmed, that specifies Tv1 neurotransmitter expression. Here, we conduct genetic and transcriptome analysis to address how other aspects of Tv1 cell fate are governed. We find that an initiator terminal selector gene triggers a feedforward loop that branches into different subroutines, each of which establishes different features of this one unique neuronal cell fate.


Assuntos
Drosophila melanogaster/genética , Redes Reguladoras de Genes , Neurônios/citologia , Animais , Axônios/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diferenciação Celular , Linhagem da Célula , Proteínas de Drosophila/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Proteínas com Homeodomínio LIM/genética , Microscopia Confocal , Neurotransmissores/genética , Análise de Sequência de RNA , Transdução de Sinais , Fatores de Transcrição/genética , Transcriptoma
4.
Development ; 146(13)2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31289041

RESUMO

During cell cycle progression, the activity of the CycE-Cdk2 complex gates S-phase entry. CycE-Cdk2 is inhibited by CDK inhibitors (CKIs) of the Cip/Kip family, which include the human p21Cip1 and Drosophila Dacapo (Dap) proteins. Both the CycE and Cip/Kip family proteins are under elaborate control via protein degradation, mediated by the Cullin-RING ligase (CRL) family of ubiquitin ligase complexes. The CRL complex SCFFbxw7/Ago targets phosphorylated CycE, whereas p21Cip1 and Dap are targeted by the CRL4Cdt2 complex, binding to the PIP degron. The role of CRL-mediated degradation of CycE and Cip/Kip proteins during CNS development is not well understood. Here, we analyse the role of ago (Fbxw7)-mediated CycE degradation, and of Dap and p21Cip1 degradation during Drosophila CNS development. We find that ago mutants display over-proliferation, accompanied by elevated CycE expression levels. By contrast, expression of PIP degron mutant Dap and p21Cip1 transgenes inhibit proliferation. However, surprisingly, this is also accompanied by elevated CycE levels. Hence, ago mutation and PIP degron Cip/Kip transgenic expression trigger opposite effects on proliferation, but similar effects on CycE levels.


Assuntos
Proliferação de Células/genética , Ciclina E/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Proteínas F-Box/genética , Mutação , Proteínas Nucleares/metabolismo , Fragmentos de Peptídeos/metabolismo , Animais , Animais Geneticamente Modificados , Sistema Nervoso Central/citologia , Sistema Nervoso Central/embriologia , Ciclina E/genética , Proteínas de Drosophila/química , Proteínas de Drosophila/fisiologia , Drosophila melanogaster , Embrião de Mamíferos , Proteínas F-Box/fisiologia , Mutação/fisiologia , Proteínas Nucleares/química , Fragmentos de Peptídeos/química , Antígeno Nuclear de Célula em Proliferação/química , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas/fisiologia , Estabilidade Proteica
5.
PLoS Biol ; 5(2): e37, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17298176

RESUMO

Neuronal specification is often seen as a multistep process: earlier regulators confer broad neuronal identity and are followed by combinatorial codes specifying neuronal properties unique to specific subtypes. However, it is still unclear whether early regulators are re-deployed in subtype-specific combinatorial codes, and whether early patterning events act to restrict the developmental potential of postmitotic cells. Here, we use the differential peptidergic fate of two lineage-related peptidergic neurons in the Drosophila ventral nerve cord to show how, in a feedforward mechanism, earlier determinants become critical players in later combinatorial codes. Amongst the progeny of neuroblast 5-6 are two peptidergic neurons: one expresses FMRFamide and the other one expresses Nplp1 and the dopamine receptor DopR. We show the HLH gene collier functions at three different levels to progressively restrict neuronal identity in the 5-6 lineage. At the final step, collier is the critical combinatorial factor that differentiates two partially overlapping combinatorial codes that define FMRFamide versus Nplp1/DopR identity. Misexpression experiments reveal that both codes can activate neuropeptide gene expression in vast numbers of neurons. Despite their partially overlapping composition, we find that the codes are remarkably specific, with each code activating only the proper neuropeptide gene. These results indicate that a limited number of regulators may constitute a potent combinatorial code that dictates unique neuronal cell fate, and that such codes show a surprising disregard for many global instructive cues.


Assuntos
Diferenciação Celular/genética , Drosophila/citologia , Drosophila/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Neurônios/metabolismo , Animais , Linhagem da Célula , Drosophila/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/fisiologia , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , FMRFamida/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Proteínas com Homeodomínio LIM , Proteínas de Membrana/metabolismo , Neurônios/classificação , Neurônios/citologia , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Receptores Dopaminérgicos/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/fisiologia
6.
Dev Cell ; 43(3): 332-348.e4, 2017 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-29112852

RESUMO

Great progress has been made in identifying transcriptional programs that establish stem cell identity. In contrast, we have limited insight into how these programs are down-graded in a timely manner to halt proliferation and allow for cellular differentiation. Drosophila embryonic neuroblasts undergo such a temporal progression, initially dividing to bud off daughters that divide once (type I), then switching to generating non-dividing daughters (type 0), and finally exiting the cell cycle. We identify six early transcription factors that drive neuroblast and type I daughter proliferation. Early factors are gradually replaced by three late factors, acting to trigger the type I→0 daughter proliferation switch and eventually to stop neuroblasts. Early and late factors regulate each other and four key cell-cycle genes, providing a logical genetic pathway for these transitions. The identification of this extensive driver-stopper temporal program controlling neuroblast lineage progression may have implications for studies in many other systems.


Assuntos
Ciclo Celular/fisiologia , Linhagem da Célula , Proliferação de Células/fisiologia , Drosophila melanogaster/citologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Células-Tronco Neurais/citologia , Animais , Diferenciação Celular/fisiologia , Linhagem da Célula/fisiologia , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo
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