PARD3 dysfunction in conjunction with dynamic HIPPO signaling drives cortical enlargement with massive heterotopia
Year: 2018
Type: preprint
Abstract: Proper organization and orderly mitosis of radial glial progenitors (RGPs) drive the formation of a laminated mammalian cortex in the correct size. However, the molecular underpinnings of the intricate process remain largely unclear. Here we show that RGP behavior and cortical development are controlled by temporally distinct actions of partitioning-defective 3 (PARD3) in concert with dynamic HIPPO signaling. RGPs lacking PARD3 exhibit developmental stage-dependent abnormal switches in division mode, resulting in an initial overproduction of RGPs located largely outside the ventricular zone at the expense of deep-layer neurons. Ectopically localized RGPs subsequently undergo accelerated and excessive neurogenesis, leading to the formation of an enlarged cortex with massive heterotopia and increased seizure susceptibility. Simultaneous removal of HIPPO pathway effectors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) suppresses cortical enlargement and heterotopia formation. These results define a dynamic regulatory program of mammalian cortical development and highlight a progenitor origin of megalencephaly with ribbon heterotopia and epilepsy.
Source: Genes & Development
Language: English
Subfield: Developmental Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Funders: Howard Hughes Medical Institute, Human Frontier Science Program, Memorial Sloan-Kettering Cancer Center, New York State Stem Cell Science, University College London, National Institutes of Health, National Institute on Drug Abuse, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Institute of Biomedical Imaging and Bioengineering
Awards: Cellular and Molecular Mechanisms of Corticogenesis, Quantitative structure-function analysis of cerebral cortex assembly at clonal level, G289723095, G3221648354, G3438518361, G470241956, G5295740231, Centrosome Regulation and Function Associated with Microcephaly, G6297060212, G7640582398, Cancer Center Support Grant, Center for Advanced Imaging Innovation and Research (CAI2R)
OpenAlex ID: W2808100189