Abstract
Loss-of-function mutations in the human oligophrenin-1 (OPHN1) gene cause intellectual disability, a prevailing neurodevelopmental condition. However, the role OPHN1 plays during neuronal development is not well understood. We investigated the role of the Drosophila OPHN1 ortholog Graf in the development of the mushroom body (MB), a key brain structure for learning and memory in insects. We show that loss of Graf causes abnormal crossing of the MB β lobe over the brain midline during metamorphosis. This defect in Graf mutants is rescued by MB-specific expression of Graf and OPHN1. Furthermore, MB α/β neuron-specific RNA interference experiments and mosaic analyses indicate that Graf acts via a cell-autonomous mechanism. Consistent with the negative regulation of epidermal growth factor receptor (EGFR)-mitogen-activated protein kinase (MAPK) signaling by Graf, activation of this pathway is required for the β-lobe midline-crossing phenotype of Graf mutants. Finally, Graf mutants have impaired olfactory long-term memory. Our findings reveal a role for Graf in MB axon development and suggest potential neurodevelopmental functions of human OPHN1.
Highlights
Intellectual disability (ID) is a neurodevelopmental disorder defined by significant impairments in both intellectual functioning and adaptive behavior that affects approximately 1% of the global population [1]
GTPase regulator associated with focal adhesion kinase-1 (Graf) is required for normal mushroom body (MB) β‐lobe extension Drosophila MBs are bilaterally symmetrical neuropil structures with their cell bodies clustered in the dorsoposterior cortex of the fly brain
Here we revealed that Drosophila Graf is required for proper development of the MB, a primary brain center in the fly for olfactory learning and memory [36]
Summary
Intellectual disability (ID) is a neurodevelopmental disorder defined by significant impairments in both intellectual functioning and adaptive behavior that affects approximately 1% of the global population [1]. Several loss-of-function mutations in OPHN1 have been found in families with syndromic ID associated with cerebellar hypoplasia and, in some cases, The OPHN1 protein belongs to the Graf (GTPase regulator associated with focal adhesion kinase-1) subfamily of GTPase-activating proteins (GAPs), whose members commonly comprise an N-terminal Bin/amphiphysin/ Rvs (BAR) domain, a pleckstrin homology (PH) domain, and a RhoGAP domain [10]. Whereas other Graf subfamily members (GRAF1, GRAF2, and GRAF3) contain a C-terminal Src homology 3 (SH3) domain, OPHN1 possesses a proline-rich domain. The BAR and PH modules of OPNH1 produce or sense membrane curvature [11], and the GAP domain inhibits Rho-family small GTPases, the master regulators of actin dynamics [3, 12, 13]. The proline-rich domain of OPHN1 interacts with
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