Figure 4.

The RBP Musashi as a master regulator of neuronal wiring. (A) Msi proteins control the morphology of photoreceptors. In the mouse retina, Msi1 and Msi2 are required for the correct formation of the outer segment (OS) in photoreceptors. Moreover, in animals lacking Msi1/2, photoreceptors have impaired light response and increased degeneration. These phenotypes are attributed to dysregulation of a Msi1/2-dependent splicing program. IS, inner segment; SE, synaptic ending. Cartoon of retina reproduced from Baden, Tom (2020); Zebrafish retina (adult); Zenodo; https://doi.org/10.5281/zenodo.3926525. (B) Msi1 controls midline crossing of precerebellar neurons in mice. The precerebellar lateral reticular neurons (LRN) and external cuneate nucleous neurons (ECN) migrate toward the ventral midline and both the processes and the cell bodies cross the ventral midline. The inferior olivary neurons (ION) also migrate toward the ventral midline, but only their processes cross the midline. In animals lacking Msi1, midline crossing and neuronal migration of IO and LR/EC neurons are impaired. Msi1 binds to the coding sequence (CDS) of the Robo3 mRNA to enhance protein levels of the Robo3 receptor. When the neurons are approaching the ventral midline, signaling from the floor plate inhibits Msi1 expression, which reduces Robo3 translation. The temporal and spatial regulation of Robo3 translation is required for the midline crossing of precerebellar neurons. (C) Msi controls axon collateral branch-specific synaptic connectivity of mechanosensory neurons in Drosophila. The mechanosensory neurons innervate bristles on the dorsal thorax of the fly and extend their axon to the ventral nerve cord (VNC). The axon forms three collateral branches that innervate the anterior (1), contralateral (2), and posterior (3) regions of the VNC, respectively. Msi specifically promotes the formation of terminal arborizations and a high number of synapses in branch 2 (open arrowhead). By contrast, in branch 3, Msi prevents ectopic synaptogenesis (filled arrowhead). These antagonistic, compartment-specific functions of Msi may depend on the regulation of different mRNA targets. For the function observed in branch 2, Msi binds to the 3′UTR of the mRNA encoding the receptor protein tyrosine phosphatase Ptp69D (bottom). Msi enhances poly(A) tailing and stability/translation of the ptp69D mRNA. For the function observed in branch 3, the relevant target(s) have not yet been identified. (D) Msi1 controls synapse size after associative learning in the Caenorhabditis elegans AVA interneuron. In wild-type animals, synapse/dendritic spine size increases during learning, and it is decreased via a Msi1-dependent mechanism during forgetting. Msi1 binds to the 3′UTR of transcripts coding for components of the actin branching regulator Arp2/3 to down-regulate its translation. The decrease in levels of the ARP2/3 complex leads to a reduced ramification of actin filaments, which correlates with the decrease in synapse size. In animals lacking Msi1, the translation of Arp2/3 complex components is not inhibited and synapse size remains high, leading to a failure to forget.