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1.
Nucleic Acids Res ; 51(19): 10218-10237, 2023 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-37697438

RESUMO

The seat of higher-order cognitive abilities in mammals, the neocortex, is a complex structure, organized in several layers. The different subtypes of principal neurons are distributed in precise ratios and at specific positions in these layers and are generated by the same neural progenitor cells (NPCs), steered by a spatially and temporally specified combination of molecular cues that are incompletely understood. Recently, we discovered that an alternatively spliced isoform of the TrkC receptor lacking the kinase domain, TrkC-T1, is a determinant of the corticofugal projection neuron (CFuPN) fate. Here, we show that the finely tuned balance between TrkC-T1 and the better known, kinase domain-containing isoform, TrkC-TK+, is cell type-specific in the developing cortex and established through the antagonistic actions of two RNA-binding proteins, Srsf1 and Elavl1. Moreover, our data show that Srsf1 promotes the CFuPN fate and Elavl1 promotes the callosal projection neuron (CPN) fate in vivo via regulating the distinct ratios of TrkC-T1 to TrkC-TK+. Taken together, we connect spatio-temporal expression of Srsf1 and Elavl1 in the developing neocortex with the regulation of TrkC alternative splicing and transcript stability and neuronal fate choice, thus adding to the mechanistic and functional understanding of alternative splicing in vivo.


Assuntos
Neocórtex , Receptor trkC , Animais , Processamento Alternativo , Mamíferos/metabolismo , Neocórtex/metabolismo , Neurônios/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptor trkC/química , Receptor trkC/genética , Receptor trkC/metabolismo , Camundongos , Linhagem Celular Tumoral
2.
Cereb Cortex ; 33(5): 1752-1767, 2023 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-35462405

RESUMO

Abnormal development of corpus callosum is relatively common and causes a broad spectrum of cognitive impairments in humans. We use acallosal Neurod2/6-deficient mice to study callosal axon guidance within the ipsilateral cerebral cortex. Initial callosal tracts form but fail to traverse the ipsilateral cingulum and are not attracted towards the midline in the absence of Neurod2/6. We show that the restoration of Ephrin-A4 (EfnA4) expression in the embryonic neocortex of Neurod2/6-deficient embryos is sufficient to partially rescue targeted callosal axon growth towards the midline. EfnA4 cannot directly mediate reverse signaling within outgrowing axons, but it forms co-receptor complexes with TrkB (Ntrk2). The ability of EfnA4 to rescue the guided growth of a subset of callosal axons in Neurod2/6-deficient mice is abolished by the co-expression of dominant negative TrkBK571N (kinase-dead) or TrkBY515F (SHC-binding deficient) variants, but not by TrkBY816F (PLCγ1-binding deficient). Additionally, EphA4 is repulsive to EfnA4-positive medially projecting axons in organotypic brain slice culture. Collectively, we suggest that EfnA4-mediated reverse signaling acts via TrkB-SHC and is required for ipsilateral callosal axon growth accuracy towards the midline downstream of Neurod family factors.


Assuntos
Neocórtex , Neuropeptídeos , Camundongos , Animais , Humanos , Corpo Caloso/metabolismo , Axônios/fisiologia , Neocórtex/metabolismo , Fibras Nervosas , Fosfotransferases/metabolismo , Neuropeptídeos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo
3.
Front Neuroanat ; 17: 1276325, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38298831

RESUMO

The Corpus Callosum (CC) is a bundle of axons connecting the cerebral hemispheres. It is the most recent structure to have appeared during evolution of placental mammals. Its development is controlled by a very complex interplay of many molecules. In humans it contains almost 80% of all commissural axons in the brain. The formation of the CC can be divided into four main stages, each controlled by numerous intracellular and extracellular molecular factors. First, a newborn neuron has to specify an axon, leave proliferative compartments, the Ventricular Zone (VZ) and Subventricular Zone (SVZ), migrate through the Intermediate Zone (IZ), and then settle at the Cortical Plate (CP). During the second stage, callosal axons navigate toward the midline within a compact bundle. Next stage is the midline crossing into contralateral hemisphere. The last step is targeting a defined area and synapse formation. This review provides an insight into these four phases of callosal axons development, as well as a description of the main molecular players involved.

4.
Cereb Cortex ; 31(12): 5470-5486, 2021 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-34259839

RESUMO

Neocortical projection neurons are generated by neural progenitor cells (NPCs) within the ventricular and subventricular zone. While early NPCs can give rise to both deep and upper layer neurons, late progenitors are restricted to upper layer neurogenesis. The molecular mechanisms controlling the differentiation potential of early versus late NPCs are unknown. Here, we report a novel function for TrkC-T1, the non-catalytic isoform of the neurotrophin receptor TrkC, that is distinct from TrkC-TK+, the full-length isoform. We provide direct evidence that TrkC-T1 regulates the switch in NPC fate from deep to upper layer neuron production. Elevated levels of TrkC-T1 in early NPCs promote the generation of deep layer neurons. Conversely, downregulation of TrkC-T1 in these cells promotes upper layer neuron fate. Furthermore, we show that TrkC-T1 exerts this control by interaction with the signaling adaptor protein ShcA. TrkC-T1 prevents the phosphorylation of Shc and the downstream activation of the MAP kinase (Erk1/2) pathway. In vivo manipulation of the activity of ShcA or Erk1/2, directly affects cortical neuron cell fate. We thus show that the generation of upper layer neurons by late progenitors is dependent on the downregulation of TrkC-T1 in late progenitor cells and the resulting activation of the ShcA/Erk1/2 pathway.


Assuntos
Neocórtex , Células-Tronco Neurais , Neocórtex/metabolismo , Células-Tronco Neurais/metabolismo , Isoformas de Proteínas/metabolismo , Receptor trkC , Transdução de Sinais/fisiologia
5.
Hum Mol Genet ; 30(22): 2068-2081, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34170319

RESUMO

Primary autosomal recessive microcephaly and Seckel syndrome spectrum disorders (MCPH-SCKS) include a heterogeneous group of autosomal recessive inherited diseases characterized by primary (congenital) microcephaly, the absence of visceral abnormalities, and a variable degree of cognitive impairment, short stature and facial dysmorphism. Recently, biallelic variants in the nuclear pore complex (NPC) component nucleoporin 85 gene (NUP85) were reported to cause steroid-resistant nephrotic syndrome (SRNS). Here, we report biallelic variants in NUP85 in two pedigrees with an MCPH-SCKS phenotype spectrum without SRNS, thereby expanding the phenotypic spectrum of NUP85-linked diseases. Structural analysis predicts the identified NUP85 variants cause conformational changes that could have an effect on NPC architecture or on its interaction with other NUPs. We show that mutant NUP85 is, however, associated with a reduced number of NPCs but unaltered nucleocytoplasmic compartmentalization, abnormal mitotic spindle morphology, and decreased cell viability and proliferation in one patient's cells. Our results also indicate the link of common cellular mechanisms involved in MCPH-SCKS spectrum disorders and NUP85-associated diseases. In addition to the previous studies, our results broaden the phenotypic spectrum of NUP85-linked human disease and propose a role for NUP85 in nervous system development.


Assuntos
Nanismo/diagnóstico , Nanismo/genética , Microcefalia/diagnóstico , Microcefalia/genética , Mutação , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Fenótipo , Encéfalo/anormalidades , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Fibroblastos/metabolismo , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , Complexo de Proteínas Formadoras de Poros Nucleares/química , Linhagem , Síndrome
6.
Neuron ; 100(5): 1097-1115.e15, 2018 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-30392800

RESUMO

The establishment of axon-dendrite polarity is fundamental for radial migration of neurons during cortex development of mammals. We demonstrate that the E3 ubiquitin ligases WW-Containing Proteins 1 and 2 (Wwp1 and Wwp2) are indispensable for proper polarization of developing neurons. We show that knockout of Wwp1 and Wwp2 results in defects in axon-dendrite polarity in pyramidal neurons, and their aberrant laminar cortical distribution. Knockout of miR-140, encoded in Wwp2 intron, engenders phenotypic changes analogous to those upon Wwp1 and Wwp2 deletion. Intriguingly, transcription of the Wwp1 and Wwp2/miR-140 loci in neurons is induced by the transcription factor Sox9. Finally, we provide evidence that miR-140 supervises the establishment of axon-dendrite polarity through repression of Fyn kinase mRNA. Our data delineate a novel regulatory pathway that involves Sox9-[Wwp1/Wwp2/miR-140]-Fyn required for axon specification, acquisition of pyramidal morphology, and proper laminar distribution of cortical neurons.


Assuntos
Polaridade Celular , Córtex Cerebral/crescimento & desenvolvimento , MicroRNAs/fisiologia , Neurônios/fisiologia , Fatores de Transcrição SOX9/fisiologia , Ubiquitina-Proteína Ligases/fisiologia , Animais , Axônios/fisiologia , Córtex Cerebral/citologia , Dendritos/fisiologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Masculino , Camundongos Knockout , MicroRNAs/genética , Neurônios/citologia , Fatores de Transcrição SOX9/genética , Ubiquitina-Proteína Ligases/genética
7.
J Neurosci Methods ; 291: 113-121, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28782628

RESUMO

BACKGROUND: Generation of different neuronal subtypes during neocortical development is the most important step in the establishment of cortical cytoarchitecture. The transcription factor Satb2 is expressed in neocortical projection neurons that send their axons intracortically as opposed to Satb2-negative neurons that preferentially project to subcortical targets. NEW METHOD: In this report, we present a novel method to carry out large scale screening for molecules that control cell fate in the developing neocortex. It is based on a Satb2Cre/+ mouse strain that expresses Cre recombinase from the Satb2 locus. RESULTS: By transfecting neuronould determine the proportion of cells that become al progenitors with a Cre-inducible reporter construct by nucleofection or in utero electroporation, we cSatb2-positive. COMPARISON WITH EXISTING METHODS: Compared to genetic tracing or lineage analysis, this method offers a fast, easy-to-perform, and reliable way of determining cell fate of newly born neurons. CONCLUSIONS: We demonstrate that the Satb2Cre/+ mouse can be applied to study factors, such as small molecule inhibitors, sh-RNAs or overexpression constructs, that can alter the proportion of Satb2-positive cells and thus play key roles in differentiation and acquisition of cell fate.


Assuntos
Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Modelos Animais , Neocórtex/citologia , Neocórtex/crescimento & desenvolvimento , Neurônios/citologia , Neurônios/metabolismo , Fatores de Transcrição/metabolismo , Animais , Diferenciação Celular/fisiologia , Células Cultivadas , Eletroporação , Citometria de Fluxo , Imuno-Histoquímica , Integrases/genética , Integrases/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/genética , Camundongos Transgênicos , Neocórtex/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Proteínas Repressoras/metabolismo , Fatores de Transcrição/genética , Transfecção , Proteínas Supressoras de Tumor/metabolismo
8.
Stem Cell Reports ; 8(2): 198-204, 2017 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-28162995

RESUMO

Gene products linked to microcephaly have been studied foremost for their role in brain development, while their function in the development of other organs has been largely neglected. Here, we report the critical role of Cdk5rap2 in maintaining the germ cell pool during embryonic development. We highlight that infertility in Cdk5rap2 mutant mice is secondary to a lack of spermatogenic cells in adult mice as a result of an early developmental defect in the germ cells through mitotic delay, prolonged cell cycle, and apoptosis.


Assuntos
Proteínas de Ciclo Celular/genética , Desenvolvimento Embrionário/genética , Células Germinativas/metabolismo , Animais , Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Feminino , Genes Letais , Estudos de Associação Genética , Genótipo , Células Germinativas/citologia , Infertilidade Masculina/genética , Masculino , Camundongos , Camundongos Knockout , Modelos Biológicos , Mutação , Fenótipo
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