Drosophila modeling of heritable neurodevelopmental disorders

Abstract

Heritable neurodevelopmental disorders are multifaceted disease conditions encompassing a wide range of symptoms including intellectual disability, cognitive dysfunction, autism and myriad other behavioral impairments. In cases where single, causative genetic defects have been identified, such as Angelman syndrome, Rett syndrome, Neurofibromatosis Type 1 and Fragile X syndrome, the classical Drosophila genetic system has provided fruitful disease models. Recent Drosophila studies have advanced our understanding of UBE3A, MECP2, NF1 and FMR1 function, respectively, in genetic, biochemical, anatomical, physiological and behavioral contexts. Investigations in Drosophila continue to provide the essential mechanistic understanding required to facilitate the conception of rational therapeutic treatments.

Figure 1. Molecular Intersections in Drosophila NDD Models

The diagram bottom row illustrates the primary genetic players in Drosophila models of Rett syndrome (RTT; MECP2, red), Angelman syndrome (AS; Dube3a, green), Fragile X syndrome (FXS; dfmr1, blue) and Neurofibromatosis Type 1 (NF1; dNF1, purple). The top row illustrates overlapping molecular interactors between the disease models, including the Rho-GEF pebble (yellow), the GTP cyclohydrolase punch (orange) and the adenylyl cyclase rutabaga (gray). Pebble is a target of the E3-ligase Dube3a, and Pebble attenuation also serves to suppress MeCP2 overexpression phenotypes. Punch is elevated by UBE3A overexpression and dfmr1 loss of function mutations. Rutabaga has long been tied to dNF1 and is likely to interact with dfmr1, as cAMP levels are altered in the Drosophila FXS model and FXS disease state [76].