PI3K regulates intraepithelial cell positioning through Rho GTP-ases in the developing neural tube

Abstract

Phosphatidylinositol 3-kinases (PI3Ks) are signal transducers of many biological processes. Class 1 A PI3Ks are hetero dimers formed by a regulatory and a catalytic subunit. We have used the developing chicken neural tube (NT) to study the roles played by PI3K during the process of cell proliferation and differentiation. Notably, we have observed that in addition to its well characterized anti apoptotic activity, PI3K also plays a crucial role in intra epithelial cell positioning, and unlike its role in survival that mainly depends on AKT, the activity in cell positioning is mediated by Rho GTPase family members. Additionally, we have observed that activating mutations of PI3K that are remarkably frequent in many human cancers, cause an unrestrained basal migration of the neuroepithelial cells that end up breaking through the basal membrane invading the surrounding mesenchymal tissue. The mechanism described in this work contribute not only to acquire a greater knowledge of the intraepithelial cell positioning process, but also give new clues on how activating mutations of PI3K contribute to cell invasion during the first stages of tumour dissemination.

Negative Regulation of mTOR Signaling Restricts Cell Proliferation in the Floor Plate

“…These findings suggest a complex transduction mechanism for the mTOR signal, and the activation of downstream components does not simply occur on a one-to-one basis. Therefore, although mTOR signal plays essential roles for the multiple aspects of the neural tube development, including cell proliferation (Figures 3, 5), differentiation (Fishwick et al, 2010), neural tube morphogenesis migration (Kobayashi et al, 2001; Torroba et al, 2018), and axon guidance (Supplementary Figure S5C), distinct intracellular factors are involved, and each critical function has to be analyzed and discussed separately (e.g., by using conditional knockout mice).…”

Neurodevelopmental disorders, like cancer, are connected to impaired chromatin remodelers, PI3K/mTOR, and PAK1-regulated MAPK

“…ASD (Amar et al, 2021 ; Busch et al, 2019 ; Iakoucheva et al, 2019 ) and cerebral palsy (Jin et al, 2020 ) have also been associated with dysregulation of Rho GTPase levels and signaling. PROS ( PIK3CA -related overgrowth spectrum) [e.g., (Martinez-Lopez et al, 2017 ; Venot et al, 2018 ; Venot and Canaud, 2017 )] appears associated with cell positioning mediated by Rho GTPase (Torroba et al, 2018 ), whereas PI3K’s contribution to cell proliferation can take place through a major Ras pathway, PI3K/PDK1/AKT/mTOR, a dominant contributor to cell growth. Cognitive impairment was associated with Rab (Ginsberg et al, 2011 ).…”