Author:
Liu Wenying Angela,Chen She,Li Zhizhong,Lee Choong Heon,Mirzaa Ghayda,Dobyns William B.,Ross M. Elizabeth,Zhang Jiangyang,Shi Song-Hai
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.
Funder
National Institutes of Health
Human Frontier Science Program
New York State Stem Cell Science
Howard Hughes Medical Institute
Publisher
Cold Spring Harbor Laboratory
Subject
Developmental Biology,Genetics
Cited by
55 articles.
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