The Warburg micro syndrome protein RAB3GAP1 modulates neuronal morphogenesis and interacts with axon elongation end ER-Golgi trafficking factors.

RAB3GAP1 is GTPase activating protein localized to the ER and Golgi compartments. In humans, mutations in RAB3GAP1 are the most common cause of Warburg Micro syndrome, a neurodevelopmental disorder associated with intellectual disability, microcephaly, and agenesis of the corpus callosum. We found that downregulation of RAB3GAP1 leads to a reduction in neurite outgrowth and complexity in human stem cell derived neurons. To further define the cellular function of RAB3GAP1, we sought to identify novel interacting proteins. We used a combination of mass spectrometry, co-immunoprecipitation and colocalization analysis and identified two novel interactors of RAB3GAP1: the axon elongation factor Dedicator of cytokinesis 7 (DOCK7) and the TATA modulatory factor 1 (TMF1) a modulator of Endoplasmic Reticulum (ER) to Golgi trafficking. To define the relationship between RAB3GAP1 and its two novel interactors, we analyzed their localization to different subcellular compartments in neuronal and non-neuronal cells with loss of RAB3GAP1. We find that RAB3GAP1 is important for the sub-cellular localization of TMF1 and DOCK7 across different compartments of the Golgi and endoplasmic reticulum. In addition, we find that loss of function mutations in RAB3GAP1 lead to dysregulation of pathways that are activated in response to the cellular stress like ATF6, MAPK, and PI3-AKT signaling. In summary, our findings suggest a novel role for RAB3GAP1 in neurite outgrowth that could encompass the regulation of proteins that control axon elongation, ER-Golgi trafficking, as well as pathways implicated in response to cellular stress.

Sex differences in development of functional connections in the face processing network.

BACKGROUND AND PURPOSE: Understanding sex differences in typical development of the face processing network is important for elucidating disruptions during atypical development in sex-linked developmental disorders like autism spectrum disorder. Based on prior sex difference studies in other cognitive domains, this study examined whether females show increased integration of core and extended face regions with age for face viewing, while males would show increased segregation. METHODS: This study used a cross-sectional design with typically developing children and adults (n = 133) and a functional MRI face localizer task. Psychophysiological interaction (PPI) analysis examined functional connectivity between canonical and extended face processing network regions with age, with greater segregation indexed by decreased core-extended region connectivity with age and greater integration indexed by increased core-extended region connectivity with age. RESULTS: PPI analysis confirmed increased segregation for males-right fusiform face area (FFA) coupling to right inferior frontal gyrus (IFG) opercular when viewing faces and left amygdala when viewing objects decreased with age. Females showed increased integration with age (increased coupling of the right FFA to right IFG opercular region and right occipital face area [OFA] to right IFG orbital when viewing faces and objects, respectively) and increased segregation (decreased coupling with age of the right OFA with IFG opercular region when viewing faces). CONCLUSIONS: Development of core and extended face processing network connectivity follows sexually dimorphic paths. These differential changes mostly occur across childhood and adolescence, with males experiencing segregation and females both segregation and integration changes in connectivity.