Titration of GLI3 repressor activity by sonic hedgehog signaling is critical for maintaining multiple adult neural stem cell and astrocyte functions
| Autor: | A. D. R. Garcia, Ralitsa Petrova, Alexandra L. Joyner |
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| Rok vydání: | 2013 |
| Předmět: |
Male
animal structures Kruppel-Like Transcription Factors Subventricular zone Mice Transgenic Nerve Tissue Proteins Mice Neural Stem Cells Zinc Finger Protein Gli3 GLI3 medicine Animals Hedgehog Proteins Sonic hedgehog Mice Knockout biology General Neuroscience Neurogenesis Articles Olfactory Bulb Hedgehog signaling pathway Neural stem cell Olfactory bulb medicine.anatomical_structure nervous system Astrocytes embryonic structures biology.protein Female Neuroscience Astrocyte Signal Transduction |
| Zdroj: | The Journal of neuroscience : the official journal of the Society for Neuroscience. 33(44) |
| ISSN: | 1529-2401 |
| Popis: | Sonic hedgehog (SHH), a key regulator of embryonic neurogenesis, signals directly to neural stem cells (NSCs) in the subventricular zone (SVZ) and to astrocytes in the adult mouse forebrain. The specific mechanism by which the GLI2 and GLI3 transcriptional activators (GLI2Aand GLI3A) and repressors (GLI2Rand GLI3R) carry out SHH signaling has not been addressed. We found that the majority of slow-cycling NSCs expressGli2andGli3,whereasGli1is restricted ventrally and all three genes are downregulated when NSCs transition into proliferating progenitors. Surprisingly, whereas conditional ablation ofSmoin postnatal glial fibrillary acidic protein-expressing cells results in cell-autonomous loss of NSCs and a progressive reduction in SVZ proliferation, without an increase in glial cell production, removal ofGli2orGli3does not alter adult SVZ neurogenesis. Significantly, removingGli3inSmoconditional mutants largely rescues neurogenesis and, conversely, expression of a constitutive GLI3Rin the absence of normalGli2andGli3abrogates neurogenesis. Thus unattenuated GLI3Ris a primary inhibitor of adult SVZ NSC function. Ablation ofGli2andGli3revealed a minor role for GLI2Rand little requirement for GLIAfunction in stimulating SVZ neurogenesis. Moreover, we found that similar rules of GLI activity apply to SHH signaling in regulating SVZ-derived olfactory bulb interneurons and maintaining cortical astrocyte function. Namely, fewer superficial olfactory bulb interneurons are generated in the absence ofGli2andGli3, whereas astrocyte partial gliosis results from an increase in GLI3R. Thus precise titration of GLIRlevels by SHH is critical to multiple functions of adult NSCs and astrocytes. |
| Databáze: | OpenAIRE |
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