@article{82de4418df7041ceb47e7370843f4354,
title = "A transcriptome-based assessment of the astrocytic dystrophin-associated complex in the developing human brain",
abstract = "Astrocytes play a critical role in regulating the interface between the cerebral vasculature and the central nervous system. Contributing to this is the astrocytic endfoot domain, a specialized structure that ensheathes the entirety of the vasculature and mediates signaling between endothelial cells, pericytes, and neurons. The astrocytic endfoot has been implicated as a critical element of the glymphatic pathway, and changes in protein expression profiles in this cellular domain are linked to Alzheimer's disease pathology. Despite this, basic physiological properties of this structure remain poorly understood including the developmental timing of its formation, and the protein components that localize there to mediate its functions. Here we use human transcriptome data from male and female subjects across several developmental stages and brain regions to characterize the gene expression profile of the dystrophin-associated complex (DAC), a known structural component of the astrocytic endfoot that supports perivascular localization of the astroglial water channel aquaporin-4. Transcriptomic profiling is also used to define genes exhibiting parallel expression profiles to DAC elements, generating a pool of candidate genes that encode gene products that may contribute to the physiological function of the perivascular astrocytic endfoot domain. We found that several genes encoding transporter proteins are transcriptionally associated with DAC genes.",
keywords = "AQP4, SCR_003302, SCR_008083, SCR_010943, astrocytes, dystrophin-associated complex, glymphatic, perivascular endfoot",
author = "Simon, {Matthew J.} and Charles Murchison and Iliff, {Jeffrey J.}",
note = "Funding Information: This study was funded by research grant support from the American Heart Association (12SDG11820014, J.J.I.), NINDS (NS089709, J.J.I.), and the Paul G. Allen Family Foundation (J.J.I.). Funding Information: With its unique location at the neurovascular interface, the end-foot is also critical to generation and maintenance of fluid and ionic homeostasis in the brain. Previous research in rats has shown that total water content in the brain decreases postnatally, and similarly the total brain amount of key ions Na1, K1, and Cl2 declines during the early postnatal weeks (Erecinska & Cherian, 2005; Vernadakis & Woodbury, 1962). Consistent with this, regulation of the extracellular space of the brain is greatest during this period. Measurement of the extracellular volume fraction in developing rats demonstrates that the most robust changes occur during the early postnatal stages (Lehmenkuhler, Sykova, Svoboda, Zilles, & Nicholson, 1993; Sykova, 2005; Vorisek & Sykova, 1997). Accordingly, several DAC proteins found at the astrocytic endfoot, including AQP4, have been shown to markedly increase expression during the first 2 weeks of postnatal development in rodents, suggesting a role for these proteins in regulating developmental changes in extracellular volume and ion homeostasis (Lunde et al., 2015; Wen et al., 1999). This notion is supported by the observation of increased total brain water with Aqp4 gene deletion (Nagelhus & Ottersen, 2013). The decline in expression of these proteins with aging also has implications for our understanding of fluid and solute movement systems in the pathophysiology of the aging brain. Funding Information: Dr. Jeffrey Iliff reports serving as a consultant for Shire Pharmaceuticals and GlaxoSmithKline. Dr. Iliff{\textquoteright}s research is also funded in part through a research collaboration with GlaxoSmithKline. Publisher Copyright: {\textcopyright} 2017 Wiley Periodicals, Inc.",
year = "2018",
month = feb,
doi = "10.1002/jnr.24082",
language = "English (US)",
volume = "96",
pages = "180--193",
journal = "Journal of Neuroscience Research",
issn = "0360-4012",
publisher = "Wiley-Liss Inc.",
number = "2",
}