The role of neuroblasts in the development of the Drosophila larval/adult brain has served as a model for the role of adult neural stem cells in normal neural development and in tumor formation. Asymmetric cell division (ACD), a critical part of the process of stem cell renewal vs. differentiation, has been extensively studied in the context of this system. This report describes a neural stem cell cancer model using the fly genes cno, a scaffold protein involved in organization of adherens junctions, and scrib, a component of the Scribble cell polarity complex that is also involved in organization of adherens junctions. Both Dmel\cno and Dmel\scrib participate in the process of asymmetric cell division, characterized primarily in neural and epithelial tissues. Classical amorphic and hypomorphic mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for both fly genes.
Dmel\cno is orthologous to the human gene AFDN; Dmel\scrib is orthologous to to human SCRIB and LRRC1. The mammalian SCRIB gene has also been characterized as a tumor suppressor. The human genes Hsap\AFDN and Hsap\SCRIB have been introduced into flies, but have not been characterized in the context of this disease model. A wild-type transgene of Hsap\SCRIB exhibits partial heterologous rescue (functional complementation) of homozygous Dmel\scrib loss-of-function phenotypes.
Assessed by generating mutant clones in otherwise wild-type tissue, loss of either cno or scrib alone in neuroblasts of the larval brain fails to produce an overproliferation phenotype. Double-mutant clones, however, do exhibit tumor-like overgrowth, resulting in formation of tumorous masses composed primarily of progenitor cells, with very few differentiated cells. Based on abnormal distribution of markers of asymmetric cell division, it is postulated that the ACD process is severely compromised in the double-mutant clones and that this could account for the increase in progenitor cells.
[updated Jan. 2019 by FlyBase; FBrf0222196]
AFDN (afadin) encodes a multi-domain protein involved in signaling and in the organization of homotypic, interneuronal, and heterotypic cell-cell adherens junctions; probably interacts with the E-cadherin-catenin system. [Gene Cards, AFDN; 2019.01.08]
SCRIB is a cytoplasmic multi-modular scaffold protein targeted to epithelial adherens junctions and neuronal presynaptic compartments. SCRIB and its orthologs in vertebrates and invertebrates participate in cell polarization (summary by Nola et al., 2008; pubmed:18716323). [from MIM:607733; 2017.08.01]
Two to one: 2 human to 1 Drosophila; the second human gene is LRRC1.
High-scoring ortholog of human AFDN (1 Drosophila to 1 human). Dmel\cno shares 32% identity and 47% similarity with the human gene.
Moderate-scoring ortholog of human SCRIB and LRRC1 (1 Drosophila to 2 human); Dmel\scrib shares 33% identity and 45% similarity with the human SCRIB gene. The human LRRC1 gene encodes a much smaller protein, corresponding to the amino end of SCRIB and Dmel\scrib; it shares 57% identity and 73% similarity with Dmel\scrib within that extent.
