Astrocytes are specialized and heterogeneous cells that contribute to central nervous system function and homeostasis. However, the mechanisms that create and maintain differences among astrocytes and allow them to fulfill particular physiological roles remain poorly defined. We reveal that neurons actively determine the features of astrocytes in the healthy adult brain and define a role for neuron-derived sonic hedgehog (Shh) in regulating the molecular and functional profile of astrocytes. Thus, the molecular and physiological program of astrocytes is not hardwired during development but, rather, depends on cues from neurons that drive and sustain their specialized properties.
PTEN is one of the most commonly lost tumor suppressors in human cancer and is known to inhibit insulin signaling. Eph receptor tyrosine kinases (RTKs) have also been implicated in cancer formation and progression, and they have diverse functions, including nervous and vascular system development. We show that in C. elegans, the VAB-1 Eph kinase domain physically interacts with and phosphorylates PTEN (DAF-18), diminishing its protein levels and function. vab-1 mutants show increased longevity and sensitivity to dauer conditions, consistent with increased DAF-18/PTEN activity and decreased insulin-like signaling. Moreover, daf-18 mutations suppress vab-1 oocyte maturation phenotypes independent of PI3K signaling. We also present evidence that DAF-18 has protein phosphatase activity to antagonize VAB-1 action. Possible implications for human cancers are discussed, based on the idea that mutually inhibitory interactions between PTEN and Eph RTKs may be conserved.
At the optic chiasm choice point, ipsilateral retinal ganglion cells (RGCs) are repelled away from the midline by guidance cues, including Ephrin-B2 and Sonic Hedgehog (Shh). Although guidance cues are normally produced by cells residing at the choice point, the mRNA for Shh is not found at the optic chiasm. Here we show that Shh protein is instead produced by contralateral RGCs at the retina, transported anterogradely along the axon, and accumulates at the optic chiasm to repel ipsilateral RGCs. In vitro, contralateral RGC axons, which secrete Shh, repel ipsilateral RGCs in a Boc- and Smo-dependent manner. Finally, knockdown of Shh in the contralateral retina causes a decrease in the proportion of ipsilateral RGCs in a non-cell-autonomous manner. These findings reveal a role for axon-axon interactions in ipsilateral RGC guidance, and they establish that remotely produced cues can act at axon guidance midline choice points.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.