Regulation of brain development by the choroid plexus and cerebrospinal fluid

A unifying goal of my research program is to understand how the human brain grows and stays healthy. The earliest born neural stem cells are located along cerebrospinal fluid (CSF)‐filled ventricles. While genes are known to regulate brain development, we found that the embryonic CSF distributes health and growth‐promoting factors that instruct neural stem cell health, division, and identity. These favorable effects of CSF are age‐dependent and emerge during the earliest stages of brain development, when the neural tube closes and the amniotic fluid captured therein forms the first CSF for the nervous system. Proteomics analyses revealed that the CSF proteome is dynamic throughout life, and thus, the same stem cells bathed in CSF obtained at other ages, display more limited cell division in other contexts. These early brain fluids contain surprisingly high levels ribosomal and translation related proteins whose expression patterns decrease in CSF as development progresses. Pairing assays of ribosome biogenesis and protein synthesis, with classic electron microscopy of the developing neural tube, led to the discovery that the protein biosynthetic machinery is dynamically regulated in neural stem cells before and after neural tube closure. Changes in these processes in developing forebrain progenitor cells are then matched by the proteomic composition of the adjacent CSF. In this manner, the nascent CSF provides a biomarker signature of the normal, healthy brain development. Using mouse genetics approaches, we found that the oncogene c‐Myc regulates ribosome biogenesis in the early forebrain, and that forced, persistent c‐Myc expression ultimately leads to a large brain and rare tumors of the choroid plexus and eye. While the role of the choroid plexus epithelium in maintaining ionic balance of CSF is reasonably well understood, surprisingly little is known about the ability of the choroid plexus to actively synthesize and secrete its own proteins and metabolites into the CSF. To better understand the sources of instructive CSF factors, we harnessed sequencing approaches to define the choroid plexus epithelial cell secretome ‐ a surprisingly large set of hundreds of proteins the choroid plexus secretes into the CSF. In the process, we discovered a regional heterogeneity between choroid plexuses in different ventricles in the brain that is evolutionarily conserved from mouse to human. Proteomics analyses revealed that this spatial heterogeneity results in the production of ventricle‐specific CSF, including the secretion of many proteins implicated in brain development and health, and which vary in an age‐dependent. We are continuing to investigate cellular heterogeneity in the choroid plexus and molecular mechanisms that regulate choroid plexus production of health and growth‐promoting factors for the brain. Support or Funding Information Alfred P. Sloan Foundation, Simons Foundation, Tommy Fuss Center, Harvard Stem Cell Institute, Pediatric Hydrocephalus Foundation, Hydrocephalus Association, Human Frontiers Science Program, National Institutes of Health, New York Stem Cell Foundation. Maria Lehtinen is a New York Stem Cell Foundation ‐ Robertson Investigator. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .