Despite recent advances in developmental biology, and the sequencing and annotation of genomes, key questions regarding the organisation of cells into embryos remain. One possibility is that uncharacterised genes having nonstandard coding arrangements and functions could provide some of the answers. Here we present the characterisation of tarsal-less (tal), a new type of noncanonical gene that had been previously classified as a putative noncoding RNA. We show that tal controls gene expression and tissue folding in Drosophila, thus acting as a link between patterning and morphogenesis. tal function is mediated by several 33-nucleotide–long open reading frames (ORFs), which are translated into 11-amino-acid–long peptides. These are the shortest functional ORFs described to date, and therefore tal defines two novel paradigms in eukaryotic coding genes: the existence of short, unprocessed peptides with key biological functions, and their arrangement in polycistronic messengers. Our discovery of tal-related short ORFs in other species defines an ancient and noncanonical gene family in metazoans that represents a new class of eukaryotic genes. Our results open a new avenue for the annotation and functional analysis of genes and sequenced genomes, in which thousands of short ORFs are still uncharacterised.
wingless and decapentaplegic signaling establishes the proximal-distal axis of Drosophila legs by activating the expression of genes such as Distalless and dachshund in broad proximal-distal domains during early leg development. However, here we show that wingless and decapentaplegic are not required throughout all of proximal-distal development. The tarsus, which has been proposed to be an ancestral structure, is instead defined by the activity of Distalless, dachshund, and a distal gradient of epidermal growth factor receptor (EGFR)-Ras signaling. Our results uncover a mechanism for appendage patterning directed by genes expressed in proximal-distal domains and possibly conserved in other arthropods and vertebrates.
In Drosophila, as in many other animals, EGFR-Ras signalling has multiple developmental roles from oogenesis to differentiation. In leg development, in particular, it has been described to be responsible for the establishment of distal leg fates in a graded manner. Here, we investigate the patterns of expression of activators of EGFR-Ras signalling, as well as some of the effectors, in order to better understand the patterning of the distal leg, and to investigate further roles of this signalling pathway. These patterns, together with genetic data obtained by different mutant conditions for EGFR-Ras members and transgene expression, suggest two rounds of signalling in leg development. Early, the EGFR ligand Vein is the main player in distal leg patterning, possibly supported later by another ligand activated by Rhomboid. Later, in a second wave of signalling when all the proximal-distal leg fates have been specified, domains of EGFR/Ras activation appear inside each leg segment to regulate Notch-mediated joint development, and also some organs such as tendons and sensory organs. This second wave relies on a ligand activated by Rhomboid.
One of the genes involved in Charcot-Marie-Tooth (CMT) disease, an inherited peripheral neuropathy, is GDAP1. In this work, we show that there is a true ortholog of this gene in Drosophila, which we have named Gdap1. By up- and down-regulation of Gdap1 in a tissue-specific manner, we show that altering its levels of expression produces changes in mitochondrial size, morphology and distribution, and neuronal and muscular degeneration. Interestingly, muscular degeneration is tissue-autonomous and not dependent on innervation. Metabolic analyses of our experimental genotypes suggest that alterations in oxidative stress are not a primary cause of the neuromuscular degeneration but a long-term consequence of the underlying mitochondrial dysfunction. Our results contribute to a better understanding of the role of mitochondria in CMT disease and pave the way to generate clinically relevant disease models to study the relationship between mitochondrial dynamics and peripheral neurodegeneration.
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