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.
Bibliographical noteFunding Information:
We thank Dr. N. Kessaris, Dr. B.G. Novitch (University of California at Los Angeles), Dr. A.K. Hadjantonakis (Memorial Sloan Kettering Cancer Center), Dr. Nicoletta Kessaris (University College London, UK), Dr. A.L. Joyner (Memorial Sloan Kettering Cancer Center), Dr. K.V. Anderson (Memorial Sloan Kettering Cancer Center), and Dr. J. Wrana (Lunenfeld-Tanenbaum Research Institute, Canada) for providing the Emx1-CreER, Rbpjfl/fl, CBF:H2B-Venus, Emx1-CreER, Yapfl/fl, and Tazfl/fl mouse lines, respectively, and the members of the Shi laboratory for valuable discussion and input. This work was supported by grants from the National Institutes of Health (R01DA024681 and R01NS085004 to S.-H.S., and P30CA008748 to Memorial Sloan Kettering Cancer Center for the Core Facilities), the Human Frontier Science Program (RGP0053/2014 to S.-H.S.), the New York State Stem Cell Science grant (N13G-232 to S.-H.S.), and the Howard Hughes Medical Institute (S.-H.S.).
- Hippo signaling
- Megalencephaly with heterotopia
- Notch signaling