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Titration of GLI3 repressor activity by sonic hedgehog signaling is critical for maintaining multiple adult neural stem cell and astrocyte functions
Journal article   Open access   Peer reviewed

Titration of GLI3 repressor activity by sonic hedgehog signaling is critical for maintaining multiple adult neural stem cell and astrocyte functions

Ralitsa Petrova, A Denise R Garcia and Alexandra L Joyner
The Journal of neuroscience, v 33(44), pp 17490-17505
30 Oct 2013
DOI: https://doi.org/10.1523/JNEUROSCI.2042-13.2013
PMID: 24174682
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1523/jneurosci.2042-13.2013View
Published, Version of Record (VoR)Maybe Open Access (Publisher Bronze),  Open

Abstract

Animals Astrocytes - pathology Astrocytes - physiology Female Hedgehog Proteins - genetics Kruppel-Like Transcription Factors - deficiency Kruppel-Like Transcription Factors - genetics Kruppel-Like Transcription Factors - metabolism Male Mice Mice, Knockout Mice, Transgenic Nerve Tissue Proteins - deficiency Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism Neural Stem Cells - physiology Olfactory Bulb - cytology Olfactory Bulb - pathology Olfactory Bulb - physiology Signal Transduction - genetics Zinc Finger Protein Gli3
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 (GLI2(A) and GLI3(A)) and repressors (GLI2(R) and GLI3(R)) carry out SHH signaling has not been addressed. We found that the majority of slow-cycling NSCs express Gli2 and Gli3, whereas Gli1 is restricted ventrally and all three genes are downregulated when NSCs transition into proliferating progenitors. Surprisingly, whereas conditional ablation of Smo in 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 of Gli2 or Gli3 does not alter adult SVZ neurogenesis. Significantly, removing Gli3 in Smo conditional mutants largely rescues neurogenesis and, conversely, expression of a constitutive GLI3(R) in the absence of normal Gli2 and Gli3 abrogates neurogenesis. Thus unattenuated GLI3(R) is a primary inhibitor of adult SVZ NSC function. Ablation of Gli2 and Gli3 revealed a minor role for GLI2(R) and little requirement for GLI(A) function 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 of Gli2 and Gli3, whereas astrocyte partial gliosis results from an increase in GLI3(R). Thus precise titration of GLI(R) levels by SHH is critical to multiple functions of adult NSCs and astrocytes.

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Collaboration types
Domestic collaboration
Web of Science research areas
Neurosciences
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