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FB2026_01
,
released March 12, 2026
Two subunits of the Drosophila retromer complex, Vps35 (orthologous to human VPS35) and Vps26 (orthologous to human VPS26A and VPS26B), have been used to characterize the role of the retromer complex in neural cell differentiation and neural stem cell tumorigenesis. The retromer complex is necessary for recycling transmembrane receptors from endosomes to the trans-Golgi network or the cell surface. This disease model was precipitated by the identification of Vps26 in a large-scale unbiased RNAi-based genetic screen for regulators of neuroblast versus progenitor cell fate decision. VPS35 is also implicated in a form of Parkinson disease (MIM:614203, FBhh0000030). Classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for both Dmel\Vps35 and Dmel\Vps26.
UAS constructs of the three human genes, Hsap\VPS35, Hsap\VPS26A and Hsap\VPS26B have been introduced into flies, but have not been characterized in the context of this disease model. Partial heterologous rescue (functional complementation) has been demonstrated for each.
In the fly system, it has been demonstrated that the retromer complex directly and specifically regulates Notch (N) receptor retrograde trafficking in neuroblast lineages, regulating the unidirectional Notch signaling from neural progenitors to neuroblasts. Under conditions of retromer dysfunction, aberrant endosomal accumulation of Notch occurs, resulting in cell-autonomous signaling activation; neural progenitors de-differentiate into neural stem-cell-like status and contribute to the formation of transplantable tumors.
[updated Jan. 2019 by FlyBase; FBrf0222196]
The retromer is a highly conserved multimeric protein complex present in all eukaryotic cells whose activity is essential for regulating the recycling and retrieval of numerous protein cargos from the endosome to trans-Golgi network or the cell surface (Vagnozzi and Pratico, 2018; pubmed:30120416).
Upon entering the endosomal-lysosomal network, internalized protein cargo has two potential destinies: either it is trafficked and delivered to the late endosomes and terminally, to lysosomes for degradation (via the ESCRT system); or, it is sorted and transported to the trans-Golgi network or the plasma membrane for reuse (via the retromer). (Hu et al., 2015; pubmed:26448863)
Many to one: 2 human to 1 Drosophila.
One to one: 1 human to 1 Drosophila.
Many to one: 2 human to 1 Drosophila.
High-scoring ortholog of human VPS35 (1 Drosophila to 1 human). Dmel\Vps35 shares 61% identity and 78% similarity with the human gene.
High-scoring ortholog of human VPS26A and VPS26B (1 Drosophila to 2 human). Dmel\Vps26 shares 65-69% identity and 77-81% similarity with the human genes.