Maria Lehtinen, Ph.D.
Assistant Professor in Pathology
Enders Building. Room 1150
300 Longwood Avenue
Boston, MA 02115
Our ultimate goal is to understand how the cerebrospinal fluid provides an adaptive and instructive signaling niche for the developing, adult, and aging brain. The neural precursor cells that build the developing brain are remarkably synchronized, yet no central command coordinating this process has been identified. Neural precursors divide immediately adjacent to cerebrospinal fluid (CSF)-filled ventricles and extend primary cilia into the CSF, suggesting that the cerebrospinal fluid may play an important role in instructing brain development. Our research recently revealed that the CSF proteome is both elaborate and dynamic, and that in addition to its passive role as a fluid cushion for the brain, the CSF actively provides a rich and adaptive library of secreted factors that help coordinate neurogenesis.
We found that during embryonic brain development, secreted factors in the CSF bind to receptors located along the apical, ventricular surface of progenitor cells, thus providing instructive cues that activate signaling pathways in these cells. Many signals in the CSF demonstrate age-dependence. For example, the expression of Igf2 in CSF peaks during embryonic brain development, during which it binds to its receptors located on the surface of neural precursor cells and instructs neural precursors to divide. Much of the proliferative effect of CSF is attributable to Igf2, but the CSF is a rich source other signaling activities as well. The ability of secreted factors in the CSF to stimulate signaling in precursors relies on appropriately positioned signaling machinery at the ventricular surface, underscoring the importance of precursor cell polarity and the integration of cell-intrinsic and cell-extrinsic signaling during brain development. Our findings raise many exciting questions about the brain-CSF interface. We are employing diverse experimental approaches that draw on molecular neuroscience, developmental neurobiology, biochemistry, and genetics to investigate:
• Active feedback regulation of the CSF environment (e.g. by the choroid plexus and blood-CSF barrier)
• Precursor cell polarity and sensing of CSF by primary cilia
• CSF signaling in neuropathological conditions
For a complete listing of publications click here.
Last Update: 11/7/2013