TALEN-based generation of a cynomolgus monkey disease model for human microcephaly

Area of Science:

• Neuroscience
• Genetics
• Primate Models

Background:

• Gene editing in non-human primates can create models for human neurological disorders.
• Existing primate models do not fully replicate human pathological and behavioral deficits.
• Microcephalin 1 (MCPH1) mutations are linked to microcephaly and intellectual disability, and MCPH1 is crucial for human brain evolution.

Purpose of the Study:

• To generate a cynomolgus monkey model with biallelic MCPH1 mutations.
• To investigate if this model recapitulates human microcephaly and associated neurological deficits.
• To explore the role of MCPH1 in primate brain evolution and microcephaly pathogenesis.

Main Methods:

• Utilized transcription activator-like effector nucleases (TALENs) for gene editing in cynomolgus monkeys.
• Generated monkeys with biallelic mutations in the MCPH1 gene.
• Characterized the resulting phenotype, including head circumference, chromosome condensation, corpus callosum development, and limb spasticity.
• Performed rescue experiments by overexpressing MCPH1 in mutated fibroblasts.

Main Results:

• Successfully generated cynomolgus monkeys with biallelic MCPH1 mutations.
• The monkey model displayed reduced head circumference, premature chromosome condensation (PCC), corpus callosum hypoplasia, and upper limb spasticity.
• Overexpression of MCPH1 in mutated dermal fibroblasts corrected the PCC syndrome, confirming MCPH1's role.

Conclusions:

• The MCPH1-mutated cynomolgus monkey serves as a valuable preclinical model for human microcephaly.
• This model aids in understanding MCPH1's role in microcephaly pathogenesis and primate brain evolution.
• Further research using this primate model can inform therapeutic strategies for human neurological disorders.