dMyc is required in retinal progenitors to prevent JNK-mediated retinal glial activation

Abstract

In the nervous system, glial cells provide crucial insulation and trophic support to neurons and are important for neuronal survival. In reaction to a wide variety of insults, glial cells respond with changes in cell morphology and metabolism to allow repair. Additionally, these cells can acquire migratory and proliferative potential. In particular, after axonal damage or pruning the clearance of axonal debris by glial cells is key for a healthy nervous system. Thus, bidirectional neuron-glial interactions are crucial in development, but little is known about the cellular sensors and signalling pathways involved. In here, we show that decreased cellular fitness in retinal progenitors caused by reduced Drosophila Myc expression triggers non cell-autonomous activation of retinal glia proliferation and overmigration. Glia migration occurs beyond its normal limit near the boundary between differentiated photoreceptors and precursor cells, extending into the progenitor domain. This overmigration is stimulated by JNK activation (and the function of its target Mmp1), while proliferative responses are mediated by Dpp/TGF-β signalling activation.

Drosophila HUWE1 Ubiquitin Ligase Regulates Endoreplication and Antagonizes JNK Signaling During Salivary Gland Development

“…In addition to its cell growth regulatory role, dMyc is also required to prevent JNK pathway activation during retinal glial cell development [ 51 ]. In salivary glands, physiological JNK activation takes place during pupal stages and is part of the disintegration process of the gland [ 52 , 53 ].…”

“…In the context of the JNK pathway, however, dHUWE1 and dMyc exhibit reciprocating functions: While dHUWE1 inhibits JNK activation, dMyc enhances JNK activation in salivary gland cells. This is likely a context-specific function of dMyc, as dMyc was shown to antagonize the JNK pathway during retinal glial cell development [ 51 ].…”

Radial Glia in Echinoderms

“…The role of the Myc family transcription factors in regulation of glial plasticity, potency, and function appears to be evolutionarily conserved in the deuterostome lineage (Tavares et al , ). For example, the vertebrate ortholog of Myc, c‐Myc, has been demonstrated to control the potency of radial glial cells.…”

The transcription factor spalt and human homologue SALL4 induce cell invasion via the dMyc-JNK pathway in Drosophila

“…In all x-z scans apical cells were up and anterior cells were left. promotes cell migration by activating JNK signaling (Ma et al, 2017a;Tavares et al, 2017). Here, overexpression of salr/SALL4 led to a downregulation of the dMyc level in the dpp-Gal4 domain (Fig.…”

“…MYC restrains breast cancer cell motility and invasion through transcriptional silencing of integrin subunits (Liu et al, 2012). In Drosophila, dMyc inhibits JNK signaling in retinal progenitors to block non-autonomous glia over-migration (Tavares et al, 2017). The Drosophila puc gene, encoding the sole JNKspecific MAPK phosphatase and inhibitor (Martin-Blanco et al, 1998), and its mammalian homologue Dusp10 are directly bound by Myc as shown in ChIP-sequencing data (Yang et al, 2013;Sabò et al, 2014).…”