Faculty Opinions recommendation of ESCRT-II controls retinal axon growth by regulating DCC receptor levels and local protein synthesis.

Retinal ganglion cell (RGC) axons of binocular animals cross the midline at the optic chiasm (OC) to grow toward their synaptic targets in the contralateral brain. Ventral anterior homeobox 1 (Vax1) plays an essential role in the development of the OC by regulating RGC axon growth in a non-cell autonomous manner. In this study, we identify an unexpected function of Vax1 that is secreted from ventral hypothalamic cells and diffuses to RGC axons, where it promotes axonal growth independent of its transcription factor activity. We demonstrate that Vax1 binds to extracellular sugar groups of the heparan sulfate proteoglycans (HSPGs) located in RGC axons. Both Vax1 binding to HSPGs and subsequent penetration into the axoplasm, where Vax1 activates local protein synthesis, are required for RGC axonal growth. Together, our findings demonstrate that Vax1 possesses a novel RGC axon growth factor activity that is critical for the development of the mammalian binocular visual system.

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DSCR1 is required for both axonal growth cone extension and steering

The Journal of Cell Biology ◽

10.1083/jcb.201510107 ◽

2016 ◽

Vol 213 (4) ◽

pp. 451-462 ◽

Cited By ~ 19

Author(s):

Wei Wang ◽

Asit Rai ◽

Eun-Mi Hur ◽

Zeev Smilansky ◽

Karen T. Chang ◽

...

Keyword(s):

Nervous System ◽

Protein Synthesis ◽

Growth Cone ◽

Actin Polymerization ◽

Axon Growth ◽

Axon Outgrowth ◽

Actin Dynamics ◽

Local Protein Synthesis ◽

Axon Extension ◽

Local Protein

Local information processing in the growth cone is essential for correct wiring of the nervous system. As an axon navigates through the developing nervous system, the growth cone responds to extrinsic guidance cues by coordinating axon outgrowth with growth cone steering. It has become increasingly clear that axon extension requires proper actin polymerization dynamics, whereas growth cone steering involves local protein synthesis. However, molecular components integrating these two processes have not been identified. Here, we show that Down syndrome critical region 1 protein (DSCR1) controls axon outgrowth by modulating growth cone actin dynamics through regulation of cofilin activity (phospho/dephospho-cofilin). Additionally, DSCR1 mediates brain-derived neurotrophic factor–induced local protein synthesis and growth cone turning. Our study identifies DSCR1 as a key protein that couples axon growth and pathfinding by dually regulating actin dynamics and local protein synthesis.

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ESCRT-II controls retinal axon growth by regulating DCC receptor levels and local protein synthesis

Open Biology ◽

10.1098/rsob.150218 ◽

2016 ◽

Vol 6 (4) ◽

pp. 150218 ◽

Cited By ~ 30

Author(s):

Filip A. Konopacki ◽

Hovy Ho-Wai Wong ◽

Asha Dwivedy ◽

Anaïs Bellon ◽

Michael D. Blower ◽

...

Keyword(s):

Protein Synthesis ◽

Axon Growth ◽

Endocytic Pathway ◽

Loss Of Function ◽

Gradient Sensing ◽

Deleted In Colorectal Cancer ◽

Local Protein Synthesis ◽

Local Protein

Endocytosis and local protein synthesis (LPS) act coordinately to mediate the chemotropic responses of axons, but the link between these two processes is poorly understood. The endosomal sorting complex required for transport (ESCRT) is a key regulator of cargo sorting in the endocytic pathway, and here we have investigated the role of ESCRT-II, a critical ESCRT component, in Xenopus retinal ganglion cell (RGC) axons. We show that ESCRT-II is present in RGC axonal growth cones (GCs) where it co-localizes with endocytic vesicle GTPases and, unexpectedly, with the Netrin-1 receptor, deleted in colorectal cancer (DCC). ESCRT-II knockdown (KD) decreases endocytosis and, strikingly, reduces DCC in GCs and leads to axon growth and guidance defects. ESCRT-II-depleted axons fail to turn in response to a Netrin-1 gradient in vitro and many axons fail to exit the eye in vivo . These defects, similar to Netrin-1/DCC loss-of-function phenotypes, can be rescued in whole ( in vitro ) or in part ( in vivo ) by expressing DCC. In addition, ESCRT-II KD impairs LPS in GCs and live imaging reveals that ESCRT-II transports mRNAs in axons. Collectively, our results show that the ESCRT-II-mediated endocytic pathway regulates both DCC and LPS in the axonal compartment and suggest that ESCRT-II aids gradient sensing in GCs by coupling endocytosis to LPS.

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