Signal amplification in growth cone gradient sensing by a double negative feedback loop among PTEN, PI(3,4,5)P3 and actomyosin

Xiong Li; Sangwoo Shim; Katherine R Hardin; Kiran G Vanaja; Hongjun Song; Andre Levchenko; Guo-Li Ming; James Q Zheng

doi:10.1016/j.mcn.2022.103772

Signal amplification in growth cone gradient sensing by a double negative feedback loop among PTEN, PI(3,4,5)P₃ and actomyosin

Mol Cell Neurosci. 2022 Dec:123:103772. doi: 10.1016/j.mcn.2022.103772. Epub 2022 Aug 31.

Authors

Xiong Li¹, Sangwoo Shim², Katherine R Hardin³, Kiran G Vanaja⁴, Hongjun Song⁵, Andre Levchenko⁴, Guo-Li Ming⁵, James Q Zheng⁶

Affiliations

¹ Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA.
² Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA; Department of Cell Biology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.
³ Department of Cell Biology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.
⁴ Department of Biomedical Engineering and Yale Systems Biology Institute, Yale University, West Haven, CT 06516, USA.
⁵ Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205, USA.
⁶ Department of Cell Biology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA. Electronic address: james.zheng@emory.edu.

Abstract

Axon guidance during neural wiring involves a series of precisely controlled chemotactic events by the motile axonal tip, the growth cone. A fundamental question is how neuronal growth cones make directional decisions in response to extremely shallow gradients of guidance cues with exquisite sensitivity. Here we report that nerve growth cones possess a signal amplification mechanism during gradient sensing process. In neuronal growth cones of Xenopus spinal neurons, phosphatidylinositol-3,4,5-trisphosphate (PIP₃), an important signaling molecule in chemotaxis, was actively recruited to the up-gradient side in response to an external gradient of brain-derived neurotrophic factor (BDNF), resulting in an intracellular gradient with approximate 30-fold amplification of the input. Furthermore, a reverse gradient of phosphatase and tensin homolog (PTEN) was induced by BDNF within the growth cone and the increased PTEN activity at the down-gradient side is required for the amplification of PIP₃ signals. Mechanistically, the establishment of both positive PIP₃ and reverse PTEN gradients depends on the filamentous actin network. Together with computational modeling, our results revealed a double negative feedback loop among PTEN, PIP₃ and actomyosin for signal amplification, which is essential for gradient sensing of neuronal growth cones in response to diffusible cues.

Keywords: Actin cytoskeleton; Asymmetric signaling; Axon guidance; Chemotaxis; Directional sensing; Phosphoinositide.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Actomyosin*
Brain-Derived Neurotrophic Factor
Chemotaxis / physiology
Feedback
Growth Cones* / physiology

Substances

Actomyosin
Brain-Derived Neurotrophic Factor

Abstract

Publication types

MeSH terms

Substances

Grants and funding