Dynamic expression of the mouse orthologue of the human amyotropic lateral sclerosis associated gene C9orf72 during central nervous system development and neuronal differentiation

• Published in: Journal of anatomy 2016-12, Vol.229 (6), p.871-891
• Main Authors: Ferguson, Ross, Serafeimidou‐Pouliou, Eleni, Subramanian, Vasanta
• Format: Article
• Language: English
• Subjects: Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Animals; Brain - embryology; Brain - growth & development; Brain - metabolism; brain development; C9orf72; C9orf72 Protein; Cell Differentiation - physiology; Central Nervous System - embryology; Central Nervous System - growth & development; Central Nervous System - metabolism; expression; Female; Gene Expression Regulation, Developmental; Humans; Mice; neuronal differentiation; Neurons - metabolism; Original; Pregnancy; Proteins - genetics; Proteins - metabolism; Rodents; spinal cord; Spinal Cord - embryology; Spinal Cord - growth & development; Spinal Cord - metabolism; Tumor Cells, Cultured
• ISSN: 0021-8782; 1469-7580
• DOI: 10.1111/joa.12526

The hexanucleotide repeat in the first intron of the C9orf72 gene is the most significant cause of amyotropic lateral sclerosis as well as some forms of fronto‐temporal dementia. The C9orf72 protein has been previously reported to be expressed in post‐mortem human brain as well as in late embryonic and some postnatal stages in mice. Herein, we present a detailed study of the distribution of C9orf72 protein in the embryonic, postnatal and adult mouse brain, spinal cord as well as during the differentiation of P19 embryonal carcinoma cells to neurons including motor neurons. We show that the expression levels of the C9orf72 transcripts in the developing and adult mouse brain as well as in differentiating neurons, are dynamic. Besides the strong expression in the cerebellum and motor cortex reported previously, we show for the first time that C9orf72 is expressed strongly in the olfactory bulb and also in the hippocampus. Our immunostaining data also reveal a hitherto unreported switch in the cellular distribution of C9orf72 from a predominantly cytoplasmic to a nucleo‐cytoplasmic distribution during corticogenesis. This switch in distribution was also observed during differentiation of the pluripotent embryonal carcinoma P19 cell line to mature neurons. Our findings have implications for interpreting the pathophysiology caused by the repeat expansions in C9orf72 in mouse models.