Chowdhury, T. A. | Search bioRxiv

bioRxiv2024

UNC-16 interacts with LRK-1 and WDFY-3 to regulate the termination of axon growth.

MAPK8IP3 (unc-16/JIP3) is a neurodevelopmental-disorder associated gene that can regulate the termination of axon growth. However, its role in this process is not well understood. Here, we report that UNC-16 promotes axon termination through a process that includes the LRK-1(LRRK-1/LRRK-2) kinase and the WDFY-3 (WDFY3/Alfy) selective autophagy protein. Genetic analysis suggests that UNC-16 promotes axon termination through an interaction between its RH1 domain and the dynein complex. Loss of unc-16 function causes accumulation of late endosomes specifically in the distal axon. Moreover, we observe synergistic interactions between loss of unc-16 function and disruptors of endolysosomal function, indicating that the endolysosomal system promotes axon termination. We also find that the axon termination defects caused by loss of UNC-16 function require the function of a genetic pathway that includes lrk-1 and wdfy-3, two genes that have been implicated in autophagy. These observations suggest a model where UNC-16 promotes axon termination by interacting with the endolysosomal system to regulate a pathway that includes LRK-1 and WDFY-3.

neuroscience↗

bioRxiv2023

Autism candidate gene rbm-26 (RBM26/27) regulates MALSU-1 to protect against mitochondrial dysfunction during axon development.

Mitochondrial dysfunction is thought to be a key component of neurodevelopmental disorders such as autism, intellectual disability, and ADHD. However, little is known about the molecular mechanisms that protect against mitochondrial dysfunction during neurodevelopment. Here, we address this question through the investigation of rbm-26, the C. elegans ortholog of the RBM27 autism candidate gene, which encodes an RNA-binding protein whose role in neurons is unknown. We report that RBM-26 (RBM26/27) protects against axonal defects by negatively regulating expression of the MALS-1 (MALSU1) mitoribosomal assembly factor. Autism-associated missense variants in RBM-26 cause a sharp decrease in RBM-26 protein expression along with defects in in axon overlap and axon degeneration that occurs during larval development. Using a biochemical screen, we identified the mRNA for the MALS-1 mitoribosomal assembly factor as a binding partner for RBM-26. Loss of RBM-26 function causes a dramatic overexpression of mals-1 mRNA and MALS-1 protein. Moreover, genetic analysis indicates that this overexpression of MALS-1 is responsible for the mitochondrial and axon degeneration defects in rbm-26 mutants. These observations reveal a mechanism that regulates expression of a mitoribosomal assembly factor to protect against axon degeneration during neurodevelopment.

neuroscience↗