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1.
Elife ; 122024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38757694

RESUMO

The fragile X syndrome (FXS) represents the most prevalent form of inherited intellectual disability and is the first monogenic cause of autism spectrum disorder. FXS results from the absence of the RNA-binding protein FMRP (fragile X messenger ribonucleoprotein). Neuronal migration is an essential step of brain development allowing displacement of neurons from their germinal niches to their final integration site. The precise role of FMRP in neuronal migration remains largely unexplored. Using live imaging of postnatal rostral migratory stream (RMS) neurons in Fmr1-null mice, we observed that the absence of FMRP leads to delayed neuronal migration and altered trajectory, associated with defects of centrosomal movement. RNA-interference-induced knockdown of Fmr1 shows that these migratory defects are cell-autonomous. Notably, the primary Fmrp mRNA target implicated in these migratory defects is microtubule-associated protein 1B (MAP1B). Knocking down MAP1B expression effectively rescued most of the observed migratory defects. Finally, we elucidate the molecular mechanisms at play by demonstrating that the absence of FMRP induces defects in the cage of microtubules surrounding the nucleus of migrating neurons, which is rescued by MAP1B knockdown. Our findings reveal a novel neurodevelopmental role for FMRP in collaboration with MAP1B, jointly orchestrating neuronal migration by influencing the microtubular cytoskeleton.


Assuntos
Movimento Celular , Proteína do X Frágil da Deficiência Intelectual , Proteínas Associadas aos Microtúbulos , Neurônios , Animais , Camundongos , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/metabolismo , Síndrome do Cromossomo X Frágil/genética , Técnicas de Silenciamento de Genes , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Neurônios/metabolismo
2.
Cell ; 186(13): 2733-2747, 2023 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-37352835

RESUMO

The cerebral cortex is the brain's outermost layer. It is responsible for processing motor and sensory information that support high-level cognitive abilities and shape personality. Its development and functional organization strongly rely on cell communication that is established via an intricate system of diffusible signals and physical contacts during development. Interfering with this cellular crosstalk can cause neurodevelopmental disorders. Here, we review how crosstalk between migrating cells and their environment influences cerebral cortex development, ranging from neurogenesis to synaptogenesis and assembly of cortical circuits.


Assuntos
Córtex Cerebral , Neurogênese , Comunicação Celular , Cognição
3.
bioRxiv ; 2023 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-36945472

RESUMO

The Fragile X Syndrome (FXS) represents the most prevalent form of inherited intellectual disability and is the first monogenic cause of Autism Spectrum Disorder. FXS results from the absence of the RNA-binding protein FMRP (Fragile X Messenger Ribonucleoprotein). Neuronal migration is an essential step of brain development allowing displacement of neurons from their germinal niches to their final integration site. The precise role of FMRP in neuronal migration remains largely unexplored. Using live imaging of postnatal Rostral Migratory Stream (RMS) neurons in Fmr1-null mice, we observed that the absence of FMRP leads to delayed neuronal migration and altered trajectory, associated with defects of centrosomal movement. RNA-interference-induced knockdown of Fmr1 shows that these migratory defects are cell-autonomous. Notably, the primary FMRP mRNA target implicated in these migratory defects is MAP1B (Microtubule-Associated Protein 1B). Knocking-down MAP1B expression effectively rescued most of the observed migratory defects. Finally, we elucidate the molecular mechanisms at play by demonstrating that the absence of FMRP induces defects in the cage of microtubules surrounding the nucleus of migrating neurons, which is rescued by MAP1B knockdown. Our findings reveal a novel neurodevelopmental role for FMRP in collaboration with MAP1B, jointly orchestrating neuronal migration by influencing the microtubular cytoskeleton.

4.
Cells ; 11(21)2022 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-36359777

RESUMO

The primary cilium (PC) is a microtubule-based tiny sensory organelle emanating from the centrosome and protruding from the surface of most eukaryotic cells, including neurons. The extremely severe phenotypes of ciliopathies have suggested their paramount importance for multiple developmental events, including brain formation. Neuronal migration is an essential step of neural development, with all neurons traveling from their site of birth to their site of integration. Neurons perform a unique type of cellular migration called cyclic saltatory migration, where their soma periodically jumps along with the stereotyped movement of their centrosome. We will review here how the role of the PC on cell motility was first described in non-neuronal cells as a guide pointing to the direction of migration. We will see then how these findings are extended to neuronal migration. In neurons, the PC appears to regulate the rhythm of cyclic saltatory neuronal migration in multiple systems. Finally, we will review recent findings starting to elucidate how extracellular cues sensed by the PC could be intracellularly transduced to regulate the machinery of neuronal migration. The PC of migrating neurons was unexpectedly discovered to display a rhythmic extracellular emergence during each cycle of migration, with this transient exposure to the external environment associated with periodic transduction of cyclic adenosine monophosphate (cAMP) signaling at the centrosome. The PC in migrating neurons thus uniquely appears as a beat maker, regulating the tempo of cyclic saltatory migration.


Assuntos
Cílios , Neurônios , Cílios/metabolismo , Movimento Celular/fisiologia , Neurônios/metabolismo , Centrossomo , Neurogênese
5.
Science ; 376(6595): eabn6204, 2022 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-35587969

RESUMO

In the forebrain, ventrally derived oligodendrocyte precursor cells (vOPCs) travel tangentially toward the cortex together with cortical interneurons. Here, we tested in the mouse whether these populations interact during embryogenesis while migrating. By coupling histological analysis of genetic models with live imaging, we show that although they are both attracted by the chemokine Cxcl12, vOPCs and cortical interneurons occupy mutually exclusive forebrain territories enriched in this chemokine. Moreover, first-wave vOPC depletion selectively disrupts the migration and distribution of cortical interneurons. At the cellular level, we found that by promoting unidirectional contact repulsion, first-wave vOPCs steered the migration of cortical interneurons away from the blood vessels to which they were both attracted, thereby allowing interneurons to reach their proper cortical territories.


Assuntos
Movimento Celular , Córtex Cerebral , Interneurônios , Neurogênese , Células Precursoras de Oligodendrócitos , Animais , Movimento Celular/genética , Córtex Cerebral/citologia , Córtex Cerebral/embriologia , Quimiocina CXCL12/metabolismo , Interneurônios/fisiologia , Camundongos , Modelos Genéticos , Neurogênese/genética , Células Precursoras de Oligodendrócitos/citologia , Células Precursoras de Oligodendrócitos/fisiologia
6.
Sci Adv ; 6(36)2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32917588

RESUMO

The primary cilium (PC) is a small centrosome-assembled organelle, protruding from the surface of most eukaryotic cells. It plays a key role in cell migration, but the underlying mechanisms are unknown. Here, we show that the PC regulates neuronal migration via cyclic adenosine 3'-5' monosphosphate (cAMP) production activating centrosomal protein kinase A (PKA). Biosensor live imaging revealed a periodic cAMP hotspot at the centrosome of embryonic, postnatal, and adult migrating neurons. Genetic ablation of the PC, or knockdown of ciliary adenylate cyclase 3, caused hotspot disappearance and migratory defects, with defective centrosome dynamics and altered nucleokinesis. Delocalization of PKA from the centrosome phenocopied the migratory defects. Our results show that the PC and centrosome form a single cAMP signaling unit dynamically regulating migration, further highlighting the centrosome as a signaling hub.


Assuntos
Adenosina , Cílios , Adenosina/metabolismo , Movimento Celular , Centrossomo/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
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