TM2D genes regulate Notch signaling and neuronal function in Drosophila

Abstract

TM2 domain containing (TM2D) proteins are conserved in metazoans and encoded by three separate genes in each model organism species that has been sequenced. Rare variants in TM2D3 are associated with Alzheimer’s disease (AD) and its fly ortholog almondex is required for embryonic Notch signaling. However, the functions of this gene family remain elusive. We knocked-out all three TM2D genes (almondex, CG11103/amaretto, CG10795/biscotti) in Drosophila and found that they share the same maternal-effect neurogenic defect. Triple null animals are not phenotypically worse than single nulls, suggesting these genes function together. Overexpression of the most conserved region of the TM2D proteins acts as a potent inhibitor of Notch signaling at the γ-secretase cleavage step. Lastly, Almondex is detected in the brain and its loss causes shortened lifespan accompanied by progressive motor and electrophysiological defects. The functional links between all three TM2D genes are likely to be evolutionarily conserved, suggesting that this entire gene family may be involved in AD.

Notch Signalling Under Maternal-to-Zygotic Transition

“…Therefore, amx is considered a component of the Notch signaling pathway. In the Drosophila genome, three paralogs of amx exist, namely biscotti ( bisc), amx , and amaretto ( amrt ) [ 52 ]. A study revealed that all three are maternal neurogenic genes, implying that each of them plays maternal roles that are essential for Notch signaling [ 52 ].…”

“…In the Drosophila genome, three paralogs of amx exist, namely biscotti ( bisc), amx , and amaretto ( amrt ) [ 52 ]. A study revealed that all three are maternal neurogenic genes, implying that each of them plays maternal roles that are essential for Notch signaling [ 52 ]. However, triple homozygotes of bisc, amx , and amrt are viable due to the maternal contribution of the corresponding proteins.…”

“…However, triple homozygotes of bisc, amx , and amrt are viable due to the maternal contribution of the corresponding proteins. These mutants do not show detectable phenotypes in development until adulthood, demonstrating that amx paralogs have no zygotic role in the postembryonic development in Drosophila [ 52 ]. The amx family genes are evolutionarily conserved, and their mammalian orthologs are designated as the TM2 domain (TM2D) containing protein genes [ 67 , 68 ].…”

“…The amx family genes are evolutionarily conserved, and their mammalian orthologs are designated as the TM2 domain (TM2D) containing protein genes [ 67 , 68 ]. bisc, amx , and amrt correspond to mammalian orthologs: TM2D1, TM2D2 , and TM2D3 , respectively [ 52 ]. These amx family genes encode predicted double-pass transmembrane proteins with a conserved DRF motif and a TM2 domain [ 68 ].…”

“…These results suggest that amx may function at the level of the Notch S3 cleaves. More recently, another epistasis analysis was conducted between various forms of Notch and a mutant amx , encoding a derivative of amx with an N-terminus truncation (AMX ECD ), a potent inhibitor of Notch signaling [ 52 ]. This study revealed that overexpression of AMX ECD suppresses the accelerated Notch signaling activity by NEXT or a ligand-dependent activated Notch, but does not suppress NICD [ 52 ].…”