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Sci Transl Med. 2015 May 6;7(286):286ra66. doi: 10.1126/scitranslmed.aaa5645.

Dysregulation of astrocyte extracellular signaling in Costello syndrome.

Author information

1
Department of Ophthalmology, University of California, San Francisco, San Francisco, CA 94143, USA.
2
Neuroscience Program, University of California, San Francisco, San Francisco, CA 94143, USA.
3
Department of Pediatrics, University of California, Davis, Sacramento, CA 95817, USA.
4
Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA.
5
Department of Pediatrics, Eli and Edythe Broad Institute for Regenerative Medicine and Stem Cell Research, and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
6
Department of Ophthalmology, University of California, San Francisco, San Francisco, CA 94143, USA. Department of Physiology, University of California, San Francisco, San Francisco, CA 94143, USA. UllianE@vision.ucsf.edu.

Abstract

Astrocytes produce an assortment of signals that promote neuronal maturation according to a precise developmental timeline. Is this orchestrated timing and signaling altered in human neurodevelopmental disorders? To address this question, the astroglial lineage was investigated in two model systems of a developmental disorder with intellectual disability caused by mutant Harvey rat sarcoma viral oncogene homolog (HRAS) termed Costello syndrome: mutant HRAS human induced pluripotent stem cells (iPSCs) and transgenic mice. Human iPSCs derived from patients with Costello syndrome differentiated to astroglia more rapidly in vitro than those derived from wild-type cell lines with normal HRAS, exhibited hyperplasia, and also generated an abundance of extracellular matrix remodeling factors and proteoglycans. Acute treatment with a farnesyl transferase inhibitor and knockdown of the transcription factor SNAI2 reduced expression of several proteoglycans in Costello syndrome iPSC-derived astrocytes. Similarly, mice in which mutant HRAS was expressed selectively in astrocytes exhibited experience-independent increased accumulation of perineuronal net proteoglycans in cortex, as well as increased parvalbumin expression in interneurons, when compared to wild-type mice. Our data indicate that astrocytes expressing mutant HRAS dysregulate cortical maturation during development as shown by abnormal extracellular matrix remodeling and implicate excessive astrocyte-to-neuron signaling as a possible drug target for treating mental impairment and enhancing neuroplasticity.

PMID:
25947161
PMCID:
PMC4474402
DOI:
10.1126/scitranslmed.aaa5645
[Indexed for MEDLINE]
Free PMC Article

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