PEA15 loss of function and defective cerebral development in the domestic cat

Autoři: Emily C. Graff aff001;  J. Nicholas Cochran aff004;  Christopher B. Kaelin aff004;  Kenneth Day aff004;  Heather L. Gray-Edwards aff002;  Rie Watanabe aff001;  Jey W. Koehler aff001;  Rebecca A. Falgoust aff002;  Jeremy W. Prokop aff004;  Richard M. Myers aff004;  Nancy R. Cox aff001;  Gregory S. Barsh aff004;  Douglas R. Martin aff002
Působiště autorů: Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, United States of America aff001;  Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University, Auburn, Alabama, United States of America aff002;  Center for Neuroscience Initiative, Auburn University, Auburn, AL, United States of America Alabama, United States of America aff003;  HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States of America aff004;  Department of Anatomy Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama, United States of America aff005
Vyšlo v časopise: PEA15 loss of function and defective cerebral development in the domestic cat. PLoS Genet 16(12): e1008671. doi:10.1371/journal.pgen.1008671
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008671


Cerebral cortical size and organization are critical features of neurodevelopment and human evolution, for which genetic investigation in model organisms can provide insight into developmental mechanisms and the causes of cerebral malformations. However, some abnormalities in cerebral cortical proliferation and folding are challenging to study in laboratory mice due to the absence of gyri and sulci in rodents. We report an autosomal recessive allele in domestic cats associated with impaired cerebral cortical expansion and folding, giving rise to a smooth, lissencephalic brain, and that appears to be caused by homozygosity for a frameshift in PEA15 (phosphoprotein expressed in astrocytes-15). Notably, previous studies of a Pea15 targeted mutation in mice did not reveal structural brain abnormalities. Affected cats, however, present with a non-progressive hypermetric gait and tremors, develop dissociative behavioral defects and aggression with age, and exhibit profound malformation of the cerebrum, with a 45% average decrease in overall brain weight, and reduction or absence of the ectosylvian, sylvian and anterior cingulate gyrus. Histologically, the cerebral cortical layers are disorganized, there is substantial loss of white matter in tracts such as the corona radiata and internal capsule, but the cerebellum is relatively spared. RNA-seq and immunohistochemical analysis reveal astrocytosis. Fibroblasts cultured from affected cats exhibit increased TNFα-mediated apoptosis, and increased FGFb-induced proliferation, consistent with previous studies implicating PEA15 as an intracellular adapter protein, and suggesting an underlying pathophysiology in which increased death of neurons accompanied by increased proliferation of astrocytes gives rise to abnormal organization of neuronal layers and loss of white matter. Taken together, our work points to a new role for PEA15 in development of a complex cerebral cortex that is only apparent in gyrencephalic species.

Klíčová slova:

Apoptosis – Astrocytes – Cats – Central nervous system – Cerebral cortex – Fibroblasts – Heterozygosity – Homozygosity


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