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1.
Elife ; 82019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31742552

RESUMO

For neural systems to function effectively, the numbers of each cell type must be proportioned properly during development. We found that conditional knockout of the mouse homeobox genes En1 and En2 in the excitatory cerebellar nuclei neurons (eCN) leads to reduced postnatal growth of the cerebellar cortex. A subset of medial and intermediate eCN are lost in the mutants, with an associated cell non-autonomous loss of their presynaptic partner Purkinje cells by birth leading to proportional scaling down of neuron production in the postnatal cerebellar cortex. Genetic killing of embryonic eCN throughout the cerebellum also leads to loss of Purkinje cells and reduced postnatal growth but throughout the cerebellar cortex. Thus, the eCN play a key role in scaling the size of the cerebellum by influencing the survival of their Purkinje cell partners, which in turn regulate production of granule cells and interneurons via the amount of sonic hedgehog secreted.


Assuntos
Proliferação de Células , Córtex Cerebelar/crescimento & desenvolvimento , Núcleos Cerebelares/citologia , Células de Purkinje/fisiologia , Animais , Técnicas de Inativação de Genes , Proteínas de Homeodomínio/genética , Camundongos , Proteínas do Tecido Nervoso/deficiência
2.
J Neurosci ; 31(9): 3186-96, 2011 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-21368030

RESUMO

The generation, differentiation, and migration of newborn neurons are critical features of normal brain development that are subject to both extracellular and intracellular regulation. However, the means of such control are only partially understood. Here, we show that expression of RTP801/REDD1, an inhibitor of mTOR (mammalian target of rapamycin) activation, is regulated during neuronal differentiation and that RTP801 functions to influence the timing of both neurogenesis and neuron migration. RTP801 levels are high in embryonic cortical neuroprogenitors, diminished in newborn neurons, and low in mature neurons. Knockdown of RTP801 in vitro and in vivo accelerates cell cycle exit by neuroprogenitors and their differentiation into neurons. It also disrupts migration of rat newborn neurons to the cortical plate and results in the ectopic localization of mature neurons. On the other hand, RTP801 overexpression delays neuronal differentiation. These findings suggest that endogenous RTP801 plays an essential role in temporal control of cortical development and in cortical patterning.


Assuntos
Movimento Celular/fisiologia , Córtex Cerebral/fisiologia , Neurogênese/fisiologia , Neurônios/citologia , Neurônios/fisiologia , Proteínas Repressoras/fisiologia , Animais , Padronização Corporal/genética , Padronização Corporal/fisiologia , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Movimento Celular/genética , Células Cultivadas , Córtex Cerebral/citologia , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/genética , Células PC12 , Ratos , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Células-Tronco/citologia , Células-Tronco/fisiologia , Fatores de Tempo , Fatores de Transcrição
3.
J Neurosci ; 31(12): 4444-55, 2011 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-21430145

RESUMO

The superior colliculus (SC)/optic tectum of the dorsal mesencephalon plays a major role in responses to visual input, yet regulation of neuronal differentiation within this layered structure is only partially understood. Here, we show that the zinc finger transcription factor Gata2 is required for normal SC development. Starting at embryonic day 15 (E15) (corresponding to the times at which neurons of the outer and intermediate layers of the SC are generated), Gata2 is transiently expressed in the rat embryonic dorsal mesencephalon within a restricted region between proliferating cells of the ventricular zone and the deepest neuronal layers of the developing SC. The Gata2-positive cells are postmitotic and lack markers of differentiated neurons, but express markers for immature neuronal precursors including Ascl1 and Pax3/7. In utero electroporation with Gata2 small hairpin RNAs at E16 into cells along the dorsal mesencephalic ventricle interferes with their normal migration into the SC and maintains them in a state characterized by retention of Pax3 expression and the absence of mature neuronal markers. Collectively, these findings indicate that Gata2 plays a required role in the transition of postmitotic neuronal precursor cells of the retinorecipient layers of the SC into mature neurons and that loss of Gata2 arrests them at an intermediate stage of differentiation.


Assuntos
Diferenciação Celular/fisiologia , Movimento Celular/fisiologia , Fator de Transcrição GATA2/fisiologia , Neurônios/fisiologia , Retina/citologia , Retina/fisiologia , Colículos Superiores/citologia , Colículos Superiores/fisiologia , Animais , Western Blotting , Eletroporação , Imuno-Histoquímica , Mesencéfalo/embriologia , Núcleos da Linha Média do Tálamo/citologia , Núcleos da Linha Média do Tálamo/fisiologia , Fator de Crescimento Neural/farmacologia , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Células PC12 , Plasmídeos/genética , RNA Interferente Pequeno/genética , Ratos , Retina/embriologia , Colículos Superiores/embriologia
4.
J Neurosci ; 30(11): 3973-82, 2010 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-20237268

RESUMO

Developmental and pathological death of neurons requires activation of a defined pathway of cell cycle proteins. However, it is unclear how this pathway is regulated and whether it is relevant in vivo. A screen for transcripts robustly induced in cultured neurons by DNA damage identified Sertad1, a Cdk4 (cyclin-dependent kinase 4) activator. Sertad1 is also induced in neurons by nerve growth factor (NGF) deprivation and Abeta (beta-amyloid). RNA interference-mediated downregulation of Sertad1 protects neurons in all three death models. Studies of NGF withdrawal indicate that Sertad1 is required to initiate the apoptotic cell cycle pathway since its knockdown blocks subsequent pathway events. Finally, we find that Sertad1 expression is required for developmental neuronal death in the cerebral cortex. Sertad1 thus appears to be essential for neuron death in trophic support deprivation in vitro and in vivo and in models of DNA damage and Alzheimer's disease. It may therefore be a suitable target for therapeutic intervention.


Assuntos
Proteínas Reguladoras de Apoptose/fisiologia , Apoptose/fisiologia , Neurônios/patologia , Neurônios/fisiologia , Proteínas Nucleares/fisiologia , Transativadores/fisiologia , Animais , Apoptose/genética , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/genética , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Córtex Cerebral/enzimologia , Córtex Cerebral/patologia , Córtex Cerebral/fisiologia , Quinase 4 Dependente de Ciclina/metabolismo , Dano ao DNA/genética , Ativação Enzimática/genética , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Camundongos , Neurônios/enzimologia , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Células PC12 , Interferência de RNA/fisiologia , Ratos , Ratos Sprague-Dawley , Transativadores/antagonistas & inibidores , Transativadores/genética , Fatores de Transcrição
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