Abstract
Genetic mosaicism, a condition in which an organ includes cells with different genotypes, is frequently present in monogenic diseases of the central nervous system caused by the random inactivation of the X-chromosome, in the case of X-linked pathologies, or by somatic mutations affecting a subset of neurons. The comprehension of the mechanisms of these diseases and of the cell-autonomous effects of specific mutations requires the generation of sparse mosaic models, in which the genotype of each neuron is univocally identified by the expression of a fluorescent protein in vivo. Here, we show a dual-color reporter system that, when expressed in a floxed mouse line for a target gene, leads to the creation of mosaics with tunable degree. We demonstrate the generation of a knockout mosaic of the autism/epilepsy related gene PTEN in which the genotype of each neuron is reliably identified, and the neuronal phenotype is accurately characterized by two-photon microscopy.
Highlights
Genetic mosaicism, a condition in which an organ includes cells with different genotypes, is frequently present in monogenic diseases of the central nervous system caused by the random inactivation of the X-chromosome, in the case of X-linked pathologies, or by somatic mutations affecting a subset of neurons
One remarkable example of how mosaicism plays a key role in defining the endophenotype of the disease is PCDH19 girl cluster epilepsy, an emerging syndrome, associated with cognitive and sensory deficiencies caused by a mosaic of expression of the protocadherin 19 gene[7]
It is not surprising that mosaic modeling has attracted wide interest, since it would allow the study of single-cell functions and cell-autonomous effects of selective overexpression/knockout (KO) in distinct cohorts of mutant and WT cells intermingled in the same environment
Summary
A condition in which an organ includes cells with different genotypes, is frequently present in monogenic diseases of the central nervous system caused by the random inactivation of the X-chromosome, in the case of X-linked pathologies, or by somatic mutations affecting a subset of neurons. Male patients with somatic mosaicism of PCDH19 present clinical manifestations identical to affected girls[7,17,18], strongly suggesting that mosaicism itself plays a pivotal role in determining this disease[7,19] Given this background, it is not surprising that mosaic modeling has attracted wide interest, since it would allow the study of single-cell functions and cell-autonomous effects of selective overexpression/knockout (KO) in distinct cohorts of mutant and WT cells intermingled in the same environment. This methodology should be transferred on the available mouse models without the need of generating mouse lines
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