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
- Precursor cell polarity and sensing of CSF by primary cilia
- CSF signaling in neuropathological conditions
About Maria Lehtinen
Maria Lehtinen received her Ph.D. in Neurobiology from Harvard University, where she trained with Azad Bonni on signaling mechanisms that regulate neuronal survival and death. She joined Anna-Elina Lehesjoki’s lab for her first postdoc at the University of Helsinki where she investigated the role of redox homeostasis in progressive myoclonus epilepsy. She then carried out a second postdoc with Christopher A. Walsh at Children’s Hospital where she discovered that secreted factors in the cerebrospinal fluid (CSF) play an active role in instructing the development of the mammalian cerebral cortex. The Lehtinen lab carries out basic and translational research on CSF-based signaling. She has been supported by the NIH, NSF, Ellison/AFAR, and the Sigrid Juselius Foundation, and is currently an Alfred P. Sloan Research Fellow.
- Lehtinen, MKand Walsh, CA, 2011. Neurogenesis at the brain-cerebrospinal fluid interface. Annual Review of Cell and Developmental Biology27:653-79.
- Lehtinen, MK*, Zappaterra, MW*, Chen, X, Yang, Y, Hill, A, Lun, M, Maynard, T, Gonzalez, D, Kim, S, Ye P, D’Ercole, AJ, Wong, ET, LaMantia, A-S, and Walsh, CA, 2011. The cerebrospinal fluid provides a proliferative niche for neural progenitor cells. Neuron 69(5):893-905. Highlighted in[A] Nature as Research Highlight 471:269; [B] Anna Buckley and Chay T Kuo:Faculty of 1000, 5 April 2011.
- Kim, S*, Lehtinen, MK*, Sessa, A, Zappaterra, MW, Cho, S-H, Gonzalez, D, Boggan, B, Austin, CA, Wijnholds, J, Gambella, MJ, Malicki, J, LaMantia, A-S, Broccoli, V, and Walsh, CA, 2010. The apical complex couples cell fate and cell survival to cerebral cortical development. Neuron 66(1):69-84. Featured asSpotlight Article, and Featured Topic in Development on Neuron website. (*co-first author)
- Lehtinen, MK, Tegelberg, S, Schipper, H, Su, H, Zukor, H, Manninen, O, Kopra, O, Joensuu, T, Hakala, P, Bonni, A, and Lehesjoki, A-E, 2009. Cystatin B deficiency sensitizes neurons to oxidative stress in progressive myoclonus epilepsy, EPM1. J Neuroscience 29(18):5910-5915.
- Lehtinen, MK*, Yuan, Z*, Boag, P, Yang, Y, Villén, J, Becker, EBE, DiBacco, S, de la Iglesia, N, Gygi, S, Blackwell, TK, and Bonni, A, 2006. A conserved MST-FOXO signaling pathway mediates oxidative stress responses and extends lifespan.Cell125:987-1001. Highlighted in [A] Nature as Research Highlight 441:788-789; [B] Jonathan Chernoff: Faculty of 1000Biology, 3 Jul 2006.