Pathological mTOR mutations impact cortical development

Human Molecular Genetics
Bartosz TarkowskiJacek Jaworski

Abstract

Several mosaic mutations of the mammalian/mechanistic target of rapamycin (mTOR) have recently been found in patients with cortical malformations, such as hemimegalencephaly (HME) and focal cortical dysplasia (FCD). Although all of them should activate mTOR signaling, comparisons of the impact of different mTOR mutations on brain development have been lacking. Also it remains unknown if any potential differences these mutations may have on cortical development are directly related to a degree of mTOR signaling increase. The present study assessed levels of mTORC1 pathway activity in cell lines and rat primary neurons overexpressing several mTOR mutants that were previously found in HME, FCD, cancer patients, and in vitro mutagenesis screens. Next, we introduced the mutants, enhancing mTORC1 signaling most potently, into developing mouse brains and assessed electroporated cell morphology and migratory phenotype using immunofluorescent staining. We observed the differential inhibition of neuronal progenitor cortical migration, which partly corresponded with a degree of mTORC1 signaling enhancement these mutants induced in cultured cells. The most potent quadruple mutant prevented most of the progenitors from entering the cortical...Continue Reading

References

Dec 1, 2006·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Gregory J WoodheadAnjen Chenn
Feb 13, 2007·Nature Methods·Mamie Z Li, Stephen J Elledge
Mar 16, 2007·Proceedings of the National Academy of Sciences of the United States of America·Jun UranoFuyuhiko Tamanoi
Sep 25, 2008·The Journal of Biological Chemistry·Yoichiro OhneTatsuya Maeda
Mar 16, 2011·The Journal of Clinical Investigation·David M FelicianoAngélique Bordey
Mar 18, 2011·EMBO Molecular Medicine·Nicole A Neuman, Elizabeth Petri Henske
Apr 8, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Malgorzata PeryczJacek Jaworski
Mar 2, 2013·Current Opinion in Neurology·Seung Tae BaekGary W Mathern
Mar 15, 2013·International Journal of Developmental Neuroscience : the Official Journal of the International Society for Developmental Neuroscience·David M FelicianoAngelique Bordey
Nov 1, 2016·IUBMB Life·Katarzyna SwitonJacek Jaworski
Nov 20, 2016·Annals of Neurology·Rahul S Desikan, A James Barkovich
Nov 28, 2016·Neuroscience·Katarzyna SwitonJacek Jaworski
Jun 24, 2017·Human Molecular Genetics·Alessandro MaginiCarla Emiliani
Dec 2, 2017·FEBS Letters·Gulistan AgirmanLaurent Nguyen

❮ Previous
Next ❯

Citations

Nov 19, 2020·International Journal of Molecular Sciences·Cecilia Zavala-TecuapetlaHiram Luna-Munguia
Apr 27, 2021·Frontiers in Neuroanatomy·Lena H Nguyen, Angélique Bordey
Nov 23, 2021·Frontiers in Neuroscience·Julia Reichard, Geraldine Zimmer-Bensch

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cell Migration in Cancer and Metastasis

Migration of cancer cells into surrounding tissue and the vasculature is an initial step in tumor metastasis. Discover the latest research on cell migration in cancer and metastasis here.

Adult Stem Cells

Adult stem cells reside in unique niches that provide vital cues for their survival, self-renewal, and differentiation. They hold great promise for use in tissue repair and regeneration as a novel therapeutic strategies. Here is the latest research.

Cell Migration

Cell migration is involved in a variety of physiological and pathological processes such as embryonic development, cancer metastasis, blood vessel formation and remoulding, tissue regeneration, immune surveillance and inflammation. Here is the latest research.