Non-canonical mTOR-Independent Role of DEPDC5 in Regulating GABAergic Network Development - Université Paris Cité Accéder directement au contenu
Article Dans Une Revue Current Biology - CB Année : 2018

Non-canonical mTOR-Independent Role of DEPDC5 in Regulating GABAergic Network Development

Résumé

Mutations in DEPDC5 are causal factors for a broad spectrum of focal epilepsies, but the underlying pathogenic mechanisms are still largely unknown. To address this question, a zebrafish depdc5 knockout model showing spontaneous epileptiform events in the brain, increased drug-induced seizure susceptibility, general hypoactivity and premature death at 2-3 weeks post fertilization as well as the expected hyperactivation of mTOR signaling was developed. Using this model, the role of DEPDC5 in brain development was investigated using an unbiased whole transcriptomic approach. Surprisingly, in addition to mTOR-associated genes, many genes involved in synaptic function, neurogenesis, axonogenesis and GABA network activity were found to be dysregulated in larval brains. Although no gross defects in brain morphology/neuron loss were observed, immunostaining of depdc5-/-brains for several GABAergic markers revealed specific defects in the fine branching of GABAergic network. Consistently, some defects in depdc5-/-could be compensated by treatment with GABA, corroborating that GABA signaling is indeed involved in DEPDC5 pathogenicity. Further, the mTOR-independent nature of the neurodevelopmental defects was demonstrated by the inability of rapamycin to rescue the defects of GABAergic networks observed in depdc5-/-brains and conversely, the inability of GABA to rescue the hypoactivity in another genetic model showing mTOR hyperactivation. This study hence provides the first in vivo evidence that DEPDC5 plays previously unknown roles apart from its canonical function as an mTOR inhibitor. Moreover, these results propose that defective neurodevelopment of GABAergic network could be a key factor in epileptogenesis when DEPDC5 is mutated.
Fichier principal
Vignette du fichier
CURRENT-BIOLOGY-D-17-01554_R3-7.pdf (3.52 Mo) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)
Loading...

Dates et versions

hal-02364352 , version 1 (14-11-2019)

Identifiants

Citer

Amrutha Swaminathan, Rahma Hassan-Abdi, Solène Renault, Aleksandra Siekierska, Raphaëlle Riché, et al.. Non-canonical mTOR-Independent Role of DEPDC5 in Regulating GABAergic Network Development. Current Biology - CB, 2018, 28 (12), pp.1924-1937.e5. ⟨10.1016/j.cub.2018.04.061⟩. ⟨hal-02364352⟩
27 Consultations
46 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More