Abstract
Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder characterized by a pronounced reduction of brain volume and intellectual disability. A current model for the microcephaly phenotype invokes a stem cell proliferation and differentiation defect, which has moved the disease into the spotlight of stem cell biology and neurodevelopmental science. Homozygous mutations of the Cyclin-dependent kinase-5 regulatory subunit-associated protein 2 gene CDK5RAP2 are one genetic cause of MCPH. To further characterize the pathomechanism underlying MCPH, we generated a conditional Cdk5rap2 LoxP/hCMV Cre mutant mouse. Further analysis, initiated on account of a lack of a microcephaly phenotype in these mutant mice, revealed the presence of previously unknown splice variants of the Cdk5rap2 gene that are at least in part accountable for the lack of microcephaly in the mice.
Highlights
Cyclin-dependent kinase-5 regulatory subunit-associated protein 2 (CDK5RAP2) has moved into the spotlight of neuroscience because of its central function in neural stem cell proliferation and brain development as well as its proposed role in mammalian brain evolution
Homozygous mutations in the CDK5RAP2 gene cause autosomal recessive primary microcephaly type 3 (MCPH3) [1,2], a rare developmental disorder of the brain characterized by a pronounced reduction of brain volume, of the neocortex, as well as intellectual disability
We report on novel splice variants of murine Cdk5rap2, which we identified in the course of the generation of a conditional mutant mouse (Cdk5rap2 LoxP/hCMV Cre)
Summary
Cyclin-dependent kinase-5 regulatory subunit-associated protein 2 (CDK5RAP2) has moved into the spotlight of neuroscience because of its central function in neural stem cell proliferation and brain development as well as its proposed role in mammalian brain evolution. Homozygous mutations in the CDK5RAP2 gene cause autosomal recessive primary microcephaly type 3 (MCPH3) [1,2], a rare developmental disorder of the brain characterized by a pronounced reduction of brain volume, of the neocortex, as well as intellectual disability (reviewed in [3,4,5]). One current model for the microcephaly phenotype of CDK5RAP2 mutations invokes a premature shift from symmetric to asymmetric neural progenitor-cell divisions with a subsequent depletion of the progenitor pool and a reduction of the final number of neurons. In contrast to the reported human phenotype, the Hertwig’s anemia mice (exon 4 inversion of the Cdk5rap gene, deletion of a large part of the γ-tubulin ring complex (γTuRC) binding domain) have microcephaly, and a hematopoietic phenotype
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