RNF152 Negatively Regulates mTOR Signalling and Blocks Cell Proliferation in the Floor Plate

Abstract

21The neural tube is composed of a number of neural progenitors and postmitotic neurons 22 distributed in a quantitatively and spatially precise manner. The floor plate, located in the ventral-23 most region of the neural tube, has a lot of unique characteristics, including a low cell proliferation 24 rate. The mechanisms by which this region-specific proliferation rate is regulated remain elusive. 25Here we show that the activity of the mTOR signalling pathway, which regulates the 26 proliferation of the neural progenitor cells, is significantly lower in the floor plate than in other 27 domains of the embryonic neural tube. We identified the forkhead-type transcription factor FoxA2 as 28 a negative regulator of mTOR signalling in the floor plate. We demonstrate that FoxA2 29 transcriptionally induces the expression of the E3 ubiquitin ligase RNF152, which together with its 30 substrate RagA, regulates cell proliferation via the mTOR pathway. Silencing of RNF152 led to the 31 aberrant upregulation of the mTOR signal and aberrant cell division in the floor plate. Taken together, 32 the present findings suggest that floor plate cell number is controlled by the negative regulation of 33 mTOR signalling through the activity of FoxA2 and its downstream effector RNF152.34 35