Abstract
During brain development, neural stem cells (NSCs) receive on-or-off signals important for regulating their amplification and reaching adequate neuron density. However, how a coordinated regulation of intracellular pathways and genetic programs is achieved has remained elusive. Here, we found that the embryonic (e) CSF contains 1012 nanoparticles/ml (77 nm diameter), some of which were identified as exosome nanovesicles that contain evolutionarily conserved molecules important for coordinating intracellular pathways. eCSF nanovesicles collected from rodent and human embryos encapsulate protein and microRNA components of the insulin-like growth factor (IGF) signaling pathway. Supplementation of eCSF nanovesicles to a mixed culture containing eNSCs activated the IGF-mammalian target of rapamycin complex 1 (mTORC1) pathway in eNSCs and expanded the pool of proliferative eNSCs. These data show that the eCSF serves as a medium for the distribution of nanovesicles, including exosomes, and the coordinated transfer of evolutionary conserved molecules that regulate eNSC amplification during corticogenesis.
Highlights
neural stem cells (NSCs) amplification during development is a critical determinant of neuron density and brain size and function, and alterations in NSC behavior have a dramatic impact on brain function at any stage of life [1]
Nanovesicles in the embryonic cerebrospinal fluid (eCSF) include exosomes and contain elements of the insulin-like growth factor (IGF) pathway To determine whether vesicles are present in the CSF of e14–15 rats during the peak corticogenesis, eCSF in the lateral ventricular cavity was labeled with a tracer dye and collected with a micropipette (Figure 1A and movie S1) as previously described by others [10,15]
We found no significant trace of blood contamination by measuring heme levels in the eCSF fraction (0.000107% of the heme level in blood)
Summary
NSC amplification during development is a critical determinant of neuron density and brain size and function, and alterations in NSC behavior have a dramatic impact on brain function at any stage of life [1]. Recent studies identified the embryonic cerebrospinal fluid (eCSF) as a reservoir of signals that directly target NSCs and regulate their proliferation [3,4]. The eCSF is essentially produced by the choroid plexus, a highly vascularized plexus of epithelial cells generated at about embryonic day 12 (e12) in rats and Carnegie stage 18 in humans [5,6]. One of the signaling molecules identified in the eCSF is insulin-like growth factor (IGF) 2, which regulates NSC proliferation through activation of IGF-1 receptors [3,4]. An array of intercellular and intracellular proteins has recently been identified in the human and rat eCSF [7]. One intriguing possibility is that eCSF-borne signaling molecules are packaged in vesicles preventing them from being degraded and allowing signal transfer to eNSCs lining the ventricular wall
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