Biology subjects

Bruce, H.

Publications and source records attributed to Bruce, H..

2 recordsLinked to original sources

bioRxiv2024

A cleaved cytosolic FOXG1 promotes excitatory neurogenesis by modulation of mitochondrial translation - a new therapeutic target for brain disorders.

The modulation of mitochondrial function is core to cell fate decisions and tissue homeostasis, yet the mechanisms regulating these processes remain poorly understood. Here, we demonstrate that mitochondrial OXPHOS activity is controlled in a tissue-specific manner through a non-canonical cytoplasmic function of the transcription factor FOXG1. A temporally regulated short cytoplasmic FOXG1 interacts with mitochondrial ribosomal proteins and enhances translation of mt-DNA-encoded OXPHOS proteins. Zebrafish and human models of early nonsense FOXG1 syndrome mutations unexpectedly produce a short C-terminal peptide. Expression of this truncated protein drives an overproduction of excitatory neurons and induces a structural, functional, and translational phenotype in mutant mitochondria. We demonstrate that this activity is a gain of function, normally carried out by a cleaved FOXG1 in wildtype. Both normal and mutant peptides are transported to the mitochondria, interact with mito-ribosomal proteins to enhance translation, thereby stimulating neurogenesis. Adjusting the dosage of the mutant peptide rescues the excitatory aspect of the FOXG1 syndrome. Our study demonstrates a novel role for cytoplasmic Foxg1 in promoting neurogenesis via the tuning of mitochondrial translation and provides the first evidence for direct tissue-specific control of OXPHOS activity. This study opens a novel therapeutic avenue for the treatment of disorders associated with mitochondrial hypoactivity. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/607559v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1b8806forg.highwire.dtl.DTLVardef@1f81e3forg.highwire.dtl.DTLVardef@89d9e1org.highwire.dtl.DTLVardef@3f7a72_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Dual functions of labial resolve the Hox logic of chelicerate head segments

Despite an abundance of gene expression surveys, comparatively little is known about Hox gene function in Chelicerata, with emphasis on the Hox logic of the anterior prosomal segments, which bear the mouthparts. Previous investigations of individual paralogs of labial (lab) and Deformed (Dfd) in the spider Parasteatoda tepidariorum have shown that these play a role in tissue maintenance of the pedipalpal segment (labial-1) and in patterning the first walking leg identity (Deformed-1), respectively. However, broader extrapolations of these data points across chelicerates are hindered by the existence of duplicated copies of Hox genes in arachnopulmonates (e.g., spiders and scorpions), which have resulted from an ancient whole genome duplication event. Here, we investigated the function of single-copy orthologs of lab in the harvestman Phalangium opilio, an exemplar of a lineage that was not subject of this whole genome duplication. Embryonic RNAi against lab resulted in homeotic transformations of pedipalps to chelicerae, as well as reduction and fusion of the pedipalpal segment with adjacent segments. To test for combinatorial function, we performed double knockdown of lab and Dfd, which results in homeotic transformation of both pedipalps and first walking legs into cheliceral identity, whereas the second walking leg is transformed into a pedipalpal identity. Taken together, these results elucidate a model for the Hox logic of head segments in Chelicerata. To substantiate the validity of this model, we additionally performed expression surveys for duplicated copies of lab and Dfd in scorpions and horseshoe crabs, toward understanding the genetic basis of a heteronomous prosoma. We show that repetition of morphologically similar appendages is correlated with uniform expression levels of the Hox genes lab and Dfd, irrespective of the number of gene copies.

developmental biology↗