The amino acid Glutamine is converted into Glutamate by a deamidation reaction catalyzed by the enzyme Glutaminase(GLS). Two isoforms of this enzyme have been described, and the GLS2 isoform is regulated by the tumor suppressorgene p53. Here, we show that the p53 family member TAp73 also drives the expression of GLS2. Specifically, we demonstratethat TAp73 regulates GLS2 during retinoic acid-induced terminal neuronal differentiation of neuroblastoma cells,and overexpression or inhibition of GLS2 modulates neuronal differentiation and intracellular levels of ATP . Moreover,inhibition of GLS activity, by removing Glutamine from the growth medium, impairs in vitro differentiation of corticalneurons. Finally, expression of GLS2 increases during mouse cerebellar development. Although, p73 is dispensable forthe in vivo expression of GLS2, TAp73 loss affects GABA and Glutamate levels in cortical neurons. Together, these findingssuggest a role for GLS2 acting, at least in part, downstream of p73 in neuronal differentiation and highlight a possible roleof p73 in regulating neurotransmitter synthesis.
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