Depdc5 knockout rat: A novel model of mTORopathy

Area of Science:

• Genetics and Molecular Biology
• Neuroscience
• Developmental Biology

Background:

• Mutations in DEPDC5, a repressor of the mTORC1 pathway, are linked to familial focal epilepsies and focal cortical dysplasia.
• Understanding the in vivo consequences of DEPDC5 deficiency is crucial for elucidating mTOR-related pathologies.

Purpose of the Study:

• To establish and characterize a global DEPDC5 knockout rat model to investigate the in vivo impact of Depdc5-deficiency.
• To explore the role of DEPDC5 in mTORC1 signaling and its implications for neurological disorders.

Main Methods:

• Generation of a global knockout rat using TALEN technology.
• Phenotypic analysis of homozygous (Depdc5(-/-)) and heterozygous (Depdc5(+/-)) embryos and rats.
• Assessment of mTORC1 pathway activation via phosphorylation of downstream effectors (S6K1, rpS6).
• Evaluation of prenatal treatment with the mTORC1 inhibitor rapamycin.

Main Results:

• Homozygous Depdc5(-/-) embryos exhibited embryonic lethality at E14.5 due to growth delay and constitutive mTORC1 hyperactivation.
• Prenatal rapamycin treatment rescued the phenotype of Depdc5(-/-) embryos.
• Heterozygous Depdc5(+/-) rats showed altered cortical neuron excitability and developed neuropathological abnormalities, including cytomegalic dysmorphic and balloon-like cells with mTORC1 upregulation, resembling human focal cortical dysplasia.

Conclusions:

• DEPDC5 deficiency leads to embryonic lethality and mTORC1 hyperactivation, confirming DEPDC5's role as an mTORC1 repressor.
• DEPDC5 knockout rats serve as a relevant model for studying mTORopathies, particularly focal cortical dysplasia.
• The findings underscore the critical role of DEPDC5 in regulating neuronal development and excitability via the mTORC1 pathway.