In mammals, there’s a burst of neurogenesis after birth that requires mTOR signalling to balance the self-renewal and differentiation activity of neural stem cells. Therefore, the loss of mTOR signalling is associated with neurodevelopmental disorders but the mechanism has been unclear. In this issue, Zhiping Wang and colleagues investigate how the E3 ubiquitin ligase UBE4B regulates the mTOR pathway during brain development by generating a conditional knockout of UBE4B in the mouse embryonic nervous system and postnatal forebrain. UBE4B-deficient mice exhibit neurodevelopmental and behavioural phenotypes and suffer lethal seizures shortly after birth. Using proteomics, the authors identity that Ube4b mutant brains have increased levels of KLHL22, an E3 ligase that degrades mTOR pathway components. The researchers employ a combination of biochemical, genetic and pharmacological approaches to show that mTOR signalling is hyperactivated in Ube4b mutants and that UBE4B negatively regulates mTOR by degrading KLHL22. Indeed, simultaneous knockout of KLHL22 or inhibition of mTOR signalling using rapamycin in utero rescues neurodevelopmental defects in Ube4b mutant animals. Together, these data demonstrate a neurodevelopmental role for UBE4B in fine-tuning of mTOR signalling activity and provide a mechanistic link between the mTOR pathway and neurodevelopment.
Breaking down the barriers between mTOR signalling and neurodevelopmental disorders
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Breaking down the barriers between mTOR signalling and neurodevelopmental disorders. Development 15 December 2022; 149 (24): e149_e2402. doi:
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