Negative regulation of brain growth by imprinted Grb10

Growth-factor receptor bound protein 10 (GRB10) is a signal adapter protein encoded by an imprinted gene, with roles in growth control, cellular proliferation, and insulin signalling. Grb10 has a unique, tissue-specific imprinted expression; the paternal copy being expressed in the CNS, whereas the maternal copy is expressed in most other adult tissues in the mouse and human. Nevertheless, although it is critical for normal behaviour in the mouse, the role of paternal Grb10 in brain growth has yet to be established. Here we investigate the brain-growth in mice lacking paternal Grb10 (Grb10+/p). Using a large sample (>400) of brains, coupled with longitudinal MRI data from adult mice, we found that both brain weight and volume in Grb10+/p mice were significantly greater relative to controls, with increasing differences with age. We then explored the cellular basis of this altered adult brain growth. Neuron (NeuN+) and glial (GFAP+) cell density were equivalent, and there was no difference in neuronal proliferation (SOX2+, BrdU+) between Grb10+/p and control mice as measured by IHC. As Grb10 is potentially linked to myelination via its interaction with IGF-1/mTOR, current investigations are focused on measuring myelination and oligodendrocytes as possible contributors to the enhanced brain growth. Future work may include measuring myelin thickness and axon width using electron microscopy. These findings represent the first clear demonstration of paternal Grb10 as a negative regulator of brain growth. This advances our understanding of genomic imprinting in the brain and may provide a novel therapeutic avenue for treatment of neurodegenerative disease.