The Cerebrospinal Fluid Provides a Proliferative Niche for Neural Progenitor Cells

Abstract

Cortical development depends on the active integration of cell autonomous and extrinsic cues, but the coordination of these processes is poorly understood. Here, we show that the apical complex protein Pals1 and Pten have opposing roles in localizing the Igf1R to the apical, ventricular domain of cerebral cortical progenitor cells. We found that the cerebrospinal fluid (CSF), which contacts this apical domain, has an age-dependent effect on proliferation, much of which is attributable to Igf2, but that CSF contains other signaling activities as well. CSF samples from patients with glioblastoma multiforme show elevated Igf2 and stimulate stem cell proliferation in an Igf2-dependent manner. Together, our findings demonstrate that the apical complex couples intrinsic and extrinsic signaling, enabling progenitors to sense and respond appropriately to diffusible CSF-borne signals distributed widely throughout the brain. The temporal control of CSF composition may have critical relevance to normal development and neuropathological conditions.

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

“…Factors within the embryonic CSF, including sonic hedgehog and choroid plexus-derived insulin-like growth factor 2, promote the proliferation of neural progenitors [59,78,90,170]. The CSF effect is optimal when age-matched CSF and tissue are combined, highlighting the dynamic nature of both the choroid plexus/CSF axis and of the intrinsic state of the responding cells [18,78]. Factors in the blood are also transported across the BCSFB.…”

Coevolution of radial glial cells and the cerebral cortex

“…Expression of ZO1 (zona occludens‐1), a tight junction‐associated protein, is not affected although the apical domain down regulates tight junctions but not adherens junctions, because in the absence of tight junctions ZO1 localizes to adherens junctions. Also, in this apical side a single cilium protrudes into the ventricular lumen, where it senses signals present in the cerebrospinal fluid that modulate the biology of these progenitor cells (Gotz and Huttner, 2005; Lehtinen and Walsh, 2011; Lehtinen et al, 2011; Paridaen and Huttner, 2014; Paridaen et al, 2013). The idea of a modulatory fine‐tuning effect mediated by the CSF has been recently addressed in a study on Otx mutants, showing not only the important role of Otx2 in choroid plexus development, but also the contribution of this structure to alterations in Wnt signaling and telencephalic proliferation (Johansson et al, 2013).…”

Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice

“…For example, the loss of activators of mTOR signaling, IgfR1, in neural precursors, results in reduced proliferation in the SVZ and microcephaly (Kappeler et al 2008;Liu et al 2009;Lehtinen et al 2011). Conversely, increased Igf activity resulted in increased proliferation in the SVZ and macrocephaly (Ye et al 2004;Lehtinen et al 2011). Two independent mTOR complexes-mTORC1 and mTORC2-are found in mammalian cells (Laplante and Sabatini 2012).…”