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1.
Cell Mol Life Sci ; 81(1): 334, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39115595

RESUMO

Mutations in the IER3IP1 (Immediate Early Response-3 Interacting Protein 1) gene can give rise to MEDS1 (Microcephaly with Simplified Gyral Pattern, Epilepsy, and Permanent Neonatal Diabetes Syndrome-1), a severe condition leading to early childhood mortality. The small endoplasmic reticulum (ER)-membrane protein IER3IP1 plays a non-essential role in ER-Golgi transport. Here, we employed secretome and cell-surface proteomics to demonstrate that the absence of IER3IP1 results in the mistrafficking of proteins crucial for neuronal development and survival, including FGFR3, UNC5B and SEMA4D. This phenomenon correlates with the distension of ER membranes and increased lysosomal activity. Notably, the trafficking of cargo receptor ERGIC53 and KDEL-receptor 2 are compromised, with the latter leading to the anomalous secretion of ER-localized chaperones. Our investigation extended to in-utero knock-down of Ier3ip1 in mouse embryo brains, revealing a morphological phenotype in newborn neurons. In summary, our findings provide insights into how the loss or mutation of a 10 kDa small ER-membrane protein can cause a fatal syndrome.


Assuntos
Retículo Endoplasmático , Complexo de Golgi , Microcefalia , Retículo Endoplasmático/metabolismo , Animais , Microcefalia/genética , Microcefalia/metabolismo , Microcefalia/patologia , Camundongos , Complexo de Golgi/metabolismo , Humanos , Mutação , Transporte Proteico , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Neurônios/metabolismo , Neurônios/patologia
2.
Biol Open ; 13(3)2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38466184

RESUMO

Here, we report the first characterization of the effects resulting from the manipulation of Soluble-Lamin Associated Protein (SLAP) expression during mammalian brain development. We found that SLAP localizes to the nuclear envelope and when overexpressed causes changes in nuclear morphology and lengthening of mitosis. SLAP overexpression in apical progenitors of the developing mouse brain altered asymmetric cell division, neurogenic commitment and neuronal migration ultimately resulting in unbalance in the proportion of upper, relative to deeper, neuronal layers. Several of these effects were also recapitulated upon Cas9-mediated knockdown. Ultimately, SLAP overexpression during development resulted in a reduction in subcortical projections of young mice and, notably, reduced their exploratory behavior. Our study shows the potential relevance of the previously uncharacterized nuclear envelope protein SLAP in neurodevelopmental disorders.


Assuntos
Comportamento Exploratório , Membrana Nuclear , Animais , Camundongos , Encéfalo , Laminas , Mamíferos , Proteínas de Membrana/genética
3.
Development ; 150(9)2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-37070770

RESUMO

Communication between the nervous and immune system is crucial for development, homeostasis and response to injury. Before the onset of neurogenesis, microglia populate the central nervous system, serving as resident immune cells over the course of life. Here, we describe new roles of an uncharacterized transcript upregulated by neurogenic progenitors during mouse corticogenesis: 4931414P19Rik (hereafter named P19). Overexpression of P19 cell-extrinsically inhibited neuronal migration and acted as chemoattractant of microglial cells. Interestingly, effects on neuronal migration were found to result directly from P19 secretion by neural progenitors triggering microglia accumulation within the P19 targeted area. Our findings highlight the crucial role of microglia during brain development and identify P19 as a previously unreported player in the neuro-immune crosstalk.


Assuntos
Microglia , Neurogênese , Animais , Camundongos , Neurogênese/fisiologia , Sistema Nervoso Central , Sistema Imunitário , Movimento Celular , Encéfalo/fisiologia
4.
Cells ; 11(11)2022 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-35681456

RESUMO

Successful embryonic and adult neurogenesis require proliferating neural stem and progenitor cells that are intrinsically and extrinsically guided into a neuronal fate. In turn, migration of new-born neurons underlies the complex cytoarchitecture of the brain. Proliferation and migration are therefore essential for brain development, homeostasis and function in adulthood. Among several tightly regulated processes involved in brain formation and function, recent evidence points to the nuclear envelope (NE) and NE-associated components as critical new contributors. Classically, the NE was thought to merely represent a barrier mediating selective exchange between the cytoplasm and nucleoplasm. However, research over the past two decades has highlighted more sophisticated and diverse roles for NE components in progenitor fate choice and migration of their progeny by tuning gene expression via interactions with chromatin, transcription factors and epigenetic factors. Defects in NE components lead to neurodevelopmental impairments, whereas age-related changes in NE components are proposed to influence neurodegenerative diseases. Thus, understanding the roles of NE components in brain development, maintenance and aging is likely to reveal new pathophysiological mechanisms for intervention. Here, we review recent findings for the previously underrepresented contribution of the NE in neuronal commitment and migration, and envision future avenues for investigation.


Assuntos
Neurogênese , Neurônios , Diferenciação Celular/fisiologia , Núcleo Celular , Neurogênese/genética , Neurônios/metabolismo , Membrana Nuclear/metabolismo
5.
Genes Dev ; 34(17-18): 1190-1209, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32820037

RESUMO

Cerebral cortical development in mammals involves a highly complex and organized set of events including the transition of neural stem and progenitor cells (NSCs) from proliferative to differentiative divisions to generate neurons. Despite progress, the spatiotemporal regulation of this proliferation-differentiation switch during neurogenesis and the upstream epigenetic triggers remain poorly known. Here we report a cortex-specific PHD finger protein, Phf21b, which is highly expressed in the neurogenic phase of cortical development and gets induced as NSCs begin to differentiate. Depletion of Phf21b in vivo inhibited neuronal differentiation as cortical progenitors lacking Phf21b were retained in the proliferative zones and underwent faster cell cycles. Mechanistically, Phf21b targets the regulatory regions of cell cycle promoting genes by virtue of its high affinity for monomethylated H3K4. Subsequently, Phf21b recruits the lysine-specific demethylase Lsd1 and histone deacetylase Hdac2, resulting in the simultaneous removal of monomethylation from H3K4 and acetylation from H3K27, respectively. Intriguingly, mutations in the Phf21b locus associate with depression and mental retardation in humans. Taken together, these findings establish how a precisely timed spatiotemporal expression of Phf21b creates an epigenetic program that triggers neural stem cell differentiation during cortical development.


Assuntos
Diferenciação Celular/genética , Córtex Cerebral/embriologia , Epigênese Genética , Células-Tronco Neurais/citologia , Neurogênese/genética , Animais , Córtex Cerebral/citologia , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos , Camundongos Endogâmicos C57BL
6.
J Comp Neurol ; 528(13): 2161-2173, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32037591

RESUMO

Smad anchor for receptor activation (SARA, zfyve9) has been classically observed in early endosomes of different cells types where it regulates vesicular transport of proteins and membrane components. Very few other members of the zinc finger FYVE domain-containing family (zfyve) have different functions other than controlling membrane trafficking. By analyzing SARA localization throughout mouse embryonic brain development, we detected that besides the endosomal localization it also targets neuronal nuclei, specifically of the cortical layers V/VI. These findings were confirmed in human brain organoids. When evaluating neuronal cell lines, we found that SARA accumulates in nuclei of PC-12 cells, but not Neuro-2a, highlighting its specificity. SARA functions as a specific marker of the deep cortical layers until the first postnatal week. This temporal regulation corresponds with the final phases of neuron differentiation, such as soma ventral translocation and axonal targeting. In sum, here we report that SARA localization during brain development is temporarily regulated, and layer specific. This defined pattern helps in the identification of early born cortical neurons. We further show that other zfyve family members (FYCO1, WDFY3, Hrs) also distribute to nuclei of different cells in the brain cortex, which raises the possibility that this might be an extended feature within the protein family.


Assuntos
Núcleo Celular/química , Proteínas de Ligação ao GTP/análise , Neocórtex/química , Neocórtex/crescimento & desenvolvimento , Animais , Animais Recém-Nascidos , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Células Cultivadas , Feminino , Proteínas de Ligação ao GTP/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neocórtex/metabolismo , Células PC12 , Ratos
7.
Nucleic Acids Res ; 47(1): 168-183, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30329130

RESUMO

Cortical development is controlled by transcriptional programs, which are orchestrated by transcription factors. Yet, stable inheritance of spatio-temporal activity of factors influencing cell fate and localization in different layers is only partly understood. Here we find that deletion of Dot1l in the murine telencephalon leads to cortical layering defects, indicating DOT1L activity and chromatin methylation at H3K79 impact on the cell cycle, and influence transcriptional programs conferring upper layer identity in early progenitors. Specifically, DOT1L prevents premature differentiation by increasing expression of genes that regulate asymmetric cell division (Vangl2, Cenpj). Loss of DOT1L results in reduced numbers of progenitors expressing genes including SoxB1 gene family members. Loss of DOT1L also leads to altered cortical distribution of deep layer neurons that express either TBR1, CTIP2 or SOX5, and less activation of transcriptional programs that are characteristic for upper layer neurons (Satb2, Pou3f3, Cux2, SoxC family members). Data from three different mouse models suggest that DOT1L balances transcriptional programs necessary for proper neuronal composition and distribution in the six cortical layers. Furthermore, because loss of DOT1L in the pre-neurogenic phase of development impairs specifically generation of SATB2-expressing upper layer neurons, our data suggest that DOT1L primes upper layer identity in cortical progenitors.


Assuntos
Proteínas de Ligação à Região de Interação com a Matriz/genética , Metiltransferases/genética , Neurogênese/genética , Neurônios/metabolismo , Fatores de Transcrição/genética , Animais , Diferenciação Celular/genética , Divisão Celular/genética , Proliferação de Células/genética , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/metabolismo , Cromatina/genética , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica no Desenvolvimento , Histona-Lisina N-Metiltransferase , Metilação , Camundongos , Neurônios/patologia , Proteínas Repressoras/genética , Fatores de Transcrição SOXD/genética , Proteínas com Domínio T , Telencéfalo/crescimento & desenvolvimento , Telencéfalo/metabolismo , Telencéfalo/patologia , Proteínas Supressoras de Tumor/genética
8.
Neurogenesis (Austin) ; 4(1): e1316887, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28573151

RESUMO

Accumulating findings have begun to unveil the important role of the endosomal machinery in the nervous system development. Endosomes have been linked to the differential segregation of cell fate determining molecules in asymmetrically dividing progenitors during neurogenesis. Additionally, the precise removal and reinsertion of membrane components through endocytic trafficking regulates the spatial and temporal distribution of signaling receptors and adhesion molecules, which determine the morphology and motility of migrating neurons. Emerging evidence suggests that the role of the endosomal sorting adaptors is dependent upon cell type and developmental stage. The repertoire of the signaling receptors and/or adhesion molecules sorted by the endosome during these processes remains to be explored. In this commentary, we will briefly address the progress in this research field.

9.
Development ; 143(17): 3143-53, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27471254

RESUMO

Emerging evidence suggests that endocytic trafficking of adhesion proteins plays a crucial role in neuronal migration during neocortical development. However, molecular insights into these processes remain elusive. Here, we study the early endosomal protein Smad anchor for receptor activation (SARA) in the developing mouse brain. SARA is enriched at the apical endfeet of radial glia of the neocortex. Although SARA knockdown did not lead to detectable neurogenic phenotypes, SARA-suppressed neurons exhibited impaired orientation and migration across the intermediate zone. Mechanistically, we show that SARA knockdown neurons exhibit increased surface expression of the L1 cell adhesion molecule. Neurons ectopically expressing L1 phenocopy the migration and orientation defects caused by SARA knockdown and display increased contact with neighboring neurites. L1 knockdown effectively rescues SARA suppression-induced phenotypes. SARA knockdown neurons eventually overcome their migration defect and enter later into the cortical plate. Nevertheless, these neurons localize at more superficial cortical layers than their control counterparts. These results suggest that SARA regulates the orientation, multipolar-to-bipolar transition and the positioning of cortical neurons via modulating surface L1 expression.


Assuntos
Proteínas de Transporte/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neocórtex/metabolismo , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Neurônios/metabolismo , Serina Endopeptidases/metabolismo , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Proteínas de Transporte/genética , Linhagem Celular , Movimento Celular/genética , Movimento Celular/fisiologia , Eletroporação , Feminino , Proteínas de Ligação ao GTP , Humanos , Immunoblotting , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Neocórtex/citologia , Molécula L1 de Adesão de Célula Nervosa/genética , Neurogênese/genética , Neurogênese/fisiologia , Gravidez , Transporte Proteico/genética , Transporte Proteico/fisiologia , Serina Endopeptidases/genética
10.
PLoS One ; 8(2): e56574, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23441206

RESUMO

IQGAP1 is a scaffolding protein that regulates spine number. We now show a differential role for IQGAP1 domains in spine morphogenesis, in which a region of the N-terminus that promotes Arp2/3-mediated actin polymerization and branching stimulates spine head formation while a region that binds to Cdc42 and Rac is required for stalk extension. Conversely, IQGAP1 rescues spine deficiency induced by expression of dominant negative Cdc42 by stimulating formation of stubby spines. Together, our observations place IQGAP1 as a crucial regulator of spine number and shape acting through the N-Wasp Arp2/3 complex, as well as upstream and downstream of Cdc42.


Assuntos
Espinhas Dendríticas/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Domínios e Motivos de Interação entre Proteínas , Proteínas Ativadoras de ras GTPase/metabolismo , Animais , Feminino , Expressão Gênica , Hipocampo/citologia , Mutação , Gravidez , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo , Proteínas Ativadoras de ras GTPase/química , Proteínas Ativadoras de ras GTPase/genética
11.
Histol Histopathol ; 27(11): 1385-94, 2012 11.
Artigo em Inglês | MEDLINE | ID: mdl-23018238

RESUMO

In this article, we review our current understanding of the biology of IQ domain-containing GTPase-Activating Protein 1, IQGAP1, a scaffolding protein with multiple binding partners, which is widely expressed among different cell types, including neurons, and capable of linking Rho-GTPase signaling with cytosleletal elements and environmental cues. Interestingly, a series of recent studies suggest that IQGAP family members have an important role in neuronal development, synaptic plasticity and nervous system disorders involving alterations in spine density.


Assuntos
Plasticidade Neuronal/genética , Neurônios/metabolismo , Proteínas Ativadoras de ras GTPase/genética , Animais , Proteínas Ativadoras de ras GTPase/metabolismo
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