Abstract
Genome association studies in human and genetic studies in mouse implicated members of the transmembrane protein 132 (TMEM132) family in multiple conditions including panic disorder, hearing loss, limb and kidney malformation. However, the presence of five TMEM132 paralogs in mammalian genomes makes it extremely challenging to reveal the full requirement for these proteins in vivo. In contrast, there is only one TMEM132 homolog, detonator (dtn), in the genome of fruit fly Drosophila melanogaster, enabling straightforward research into its in vivo function. In the current study, we generate multiple loss-of-function dtn mutant fly strains through a polycistronic tRNA-gRNA approach, and show that most embryos lacking both maternal and paternal dtn fail to hatch into larvae, indicating an essential role of dtn in Drosophila reproduction.
Highlights
Our understanding of the molecular mechanisms underlying normal development and physiological function of animals including humans is crucial for developing strategies to prevent birth defects and treating diseases with genetic components such as autism and autoimmune diseases
Protein sequences for human transmembrane protein 132 (TMEM132) family of proteins and Drosophila melanogaster dtn were downloaded from http://www.ensembl.org
SMART protein structure analysis suggested that this 1320-amino-acid protein contained a N-terminal signal peptide, two extracellular motifs conserved among TMEM132 proteins (TMEM132D_N and TMEM132 domains), a transmembrane domain (TM), and a coiled-coil domain in the intracellular tail (Fig 1)
Summary
Our understanding of the molecular mechanisms underlying normal development and physiological function of animals including humans is crucial for developing strategies to prevent birth defects and treating diseases with genetic components such as autism and autoimmune diseases. The precise alterations of individual genes through reverse genetics have been difficult in these models until the new clustered regulatory palindromic interspaced short repeats (CRISPR)/ CrRNA associated protein 9 (Cas9)-based mutagenesis approach revolutionized genetic manipulations in many model animals [3] Another approach that has been instrumental for the identification of genes involved in disease pathogenesis is the association studies linking human diseases to specific genomic loci [4]. TMEM132A has not been associated with human diseases, a recent study in mice suggested that loss of Tmem132a resulted in preweaning lethality and defects in multiple tissues including the neural tube, limbs and kidneys [14] These studies indicate that the TMEM132 family of proteins plays critical roles in the development and function of multiple systems. These results suggest that dtn plays an important role in Drosophila reproduction
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