While astrocytes are the most abundant cells in the brain, their role in cognition and disease remains very poorly studied.  What is known is that they play a vital role in regulating extracellular signaling and the development and maturation of neurons.  It follows that abnormalities in glia might contribute to certain neural developmental disorders.  One such disease is Costello syndrome which is caused by mutations in the HRAS gene. Erik Ullian et al. used mutant HRAS human induced pluripotent stem cells (iPSCs) and transgenic mice to study the lineage of astroglia in this disease.

The researchers found that iPSCs from humans with Costello syndrome behaved differently than those from healthy controls in several ways. First, they differentiated into astroglia more quickly, second, they grew larger, and finally, they produced more extracellular remodeling factors and proteoglycans.  Similarly, mice who had astrocyte selective mutations in HRAS showed increased proteoglycans in cortex.  These changes likely cause the abnormal development observed in Costello syndrome.

Screen Shot 2017-05-08 at 5.37.12 PMTo confirm that the changes in astroglia were being caused by RAS signaling the researchers treated the iPSCs with farnesyl transferase inhibitor which selectively blocks RAS.  After two weeks of treatment they found that quantities of extracellular proteoglycans decreased and that the transcription factors associated with normal development were not affected.  These results offer new insight into the etiology of a rare but debilitating developmental disorder and point to a possible pharmacological therapy.

To learn more about Dr. Ullian’s research, please attend his talk on Tuesday, May 9, 2017 at 4pm in the CNCB Marilyn G. Farquhar Seminar Room.




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