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1.
Proc Natl Acad Sci U S A ; 111(34): 12438-43, 2014 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-25114218

RESUMO

The apical domain of embryonic (radial glia) and adult (B1 cells) neural stem cells (NSCs) contains a primary cilium. This organelle has been suggested to function as an antenna for the detection of morphogens or growth factors. In particular, primary cilia are essential for Hedgehog (Hh) signaling, which plays key roles in brain development. Their unique location facing the ventricular lumen suggests that primary cilia in NSCs could play an important role in reception of signals within the cerebrospinal fluid. Surprisingly, ablation of primary cilia using conditional alleles for genes essential for intraflagellar transport [kinesin family member 3A (Kif3a) and intraflagellar transport 88 (Ift88)] and Cre drivers that are activated at early [Nestin; embryonic day 10.5 (E10.5)] and late [human glial fibrillary acidic protein (hGFAP); E13.5] stages of mouse neural development resulted in no apparent developmental defects. Neurogenesis in the ventricular-subventricular zone (V-SVZ) shortly after birth was also largely unaffected, except for a restricted ventral domain previously known to be regulated by Hh signaling. However, Kif3a and Ift88 genetic ablation also disrupts ependymal cilia, resulting in hydrocephalus by postnatal day 4. To directly study the role of B1 cells' primary cilia without the confounding effects of hydrocephalus, we stereotaxically targeted elimination of Kif3a from a subpopulation of radial glia, which resulted in ablation of primary cilia in a subset of B1 cells. Again, this experiment resulted in decreased neurogenesis only in the ventral V-SVZ. Primary cilia ablation led to disruption of Hh signaling in this subdomain. We conclude that primary cilia are required in a specific Hh-regulated subregion of the postnatal V-SVZ.


Assuntos
Cílios/fisiologia , Células-Tronco Neurais/classificação , Células-Tronco Neurais/ultraestrutura , Animais , Animais Recém-Nascidos , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Proliferação de Células , Células-Tronco Embrionárias/classificação , Células-Tronco Embrionárias/metabolismo , Células-Tronco Embrionárias/ultraestrutura , Feminino , Técnicas de Silenciamento de Genes , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Proteínas Hedgehog/fisiologia , Humanos , Cinesinas/antagonistas & inibidores , Cinesinas/genética , Cinesinas/metabolismo , Camundongos , Camundongos Transgênicos , Nestina/genética , Nestina/metabolismo , Células-Tronco Neurais/metabolismo , Neurogênese/fisiologia , Gravidez , Transdução de Sinais , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
2.
Neurobiol Aging ; 35(7): 1669-79, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24559648

RESUMO

Previous studies have demonstrated an age related decline in the size of the neural stem cell (NSC) pool and a decrease in neural progenitor cell proliferation, however, the mechanisms underlying these changes are unclear. In contrast to previous reports, we report that the numbers of NSCs is unchanged in the old age subependyma and the apparent loss is because of reduced proliferative potential in the aged stem cell niche. Transplantation studies reveal that the proliferation kinetics and migratory behavior of neural precursor cells are dependent on the age of the host animal and independent of the age of the donor cells suggesting that young and old age neural precursors are not intrinsically different. Factors from the young stem cell niche rescue the numbers of NSC colonies derived from old age subependyma and enhance progenitor cell proliferation in vivo in old age mice. Finally, we report a loss of Wnt signaling in the old age stem cell niche that underlies the lack of expansion of the NSC pool after stroke.


Assuntos
Envelhecimento/patologia , Proliferação de Células , Epêndima/citologia , Células-Tronco Neurais/citologia , Nicho de Células-Tronco/fisiologia , Animais , Movimento Celular , Células Cultivadas , Epêndima/fisiologia , Camundongos , Camundongos Endogâmicos , Células-Tronco Neurais/fisiologia , Nicho de Células-Tronco/genética , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia , Via de Sinalização Wnt/genética , Via de Sinalização Wnt/fisiologia
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