Temporal regulation of axonal repulsion by alternative splicing of a conserved microexon in mammalian Robo1 and Robo2

ELife
Verity JohnsonZhe Chen

Abstract

Proper connectivity of the nervous system requires temporal and spatial control of axon guidance signaling. As commissural axons navigate across the CNS midline, ROBO-mediated repulsion has traditionally been thought to be repressed before crossing, and then to become upregulated after crossing. The regulation of the ROBO receptors involves multiple mechanisms that control protein expression, trafficking, and activity. Here, we report that mammalian ROBO1 and ROBO2 are not uniformly inhibited precrossing and are instead subject to additional temporal control via alternative splicing at a conserved microexon. The NOVA splicing factors regulate the developmental expression of ROBO1 and ROBO2 variants with small sequence differences and distinct guidance activities. As a result, ROBO-mediated axonal repulsion is activated early in development to prevent premature crossing and becomes inhibited later to allow crossing. Postcrossing, the ROBO1 and ROBO2 isoforms are disinhibited to prevent midline reentry and to guide postcrossing commissural axons to distinct mediolateral positions.

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Citations

Jan 11, 2020·Wiley Interdisciplinary Reviews. RNA·Sika Zheng
Dec 18, 2020·The FEBS Journal·Carlos Wilson, Alfredo Cáceres
Jun 15, 2020·Current Opinion in Genetics & Development·Thomas Gonatopoulos-Pournatzis, Benjamin J Blencowe
Apr 16, 2021·Advanced Science·Qian-Qian WanKai Jiao
Oct 21, 2020·Seminars in Cell & Developmental Biology·Ryan A SzetoCleber A Trujillo
Jun 23, 2021·Wiley Interdisciplinary Reviews. RNA·Jee-San LeeStéphane Richard
Jul 13, 2021·Frontiers in Cell and Developmental Biology·Maud WurmserSara Ivy Wilson
Aug 5, 2021·Cell Reports·Bikash ChoudharyAdam D Norris
Aug 21, 2020·Developmental Biology·Madhavi Gorla, Greg J Bashaw

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Methods Mentioned

BETA
electrophoresis
genotyping
GTPases
GTPase
PCR
fluorescence microscopy
pull-down

Software Mentioned

Prism7
ImageJ
SLIT
Nova
ZEN

Related Concepts

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