Myo5b knockout mice as a model of microvillus inclusion disease

• Published in: Scientific reports Vol. 5; no. 1; p. 12312
• Main Authors: Cartón-García, Fernando, Overeem, Arend W., Nieto, Rocio, Bazzocco, Sarah, Dopeso, Higinio, Macaya, Irati, Bilic, Josipa, Landolfi, Stefania, Hernandez-Losa, Javier, Schwartz, Simo, Ramon y Cajal, Santiago, van Ijzendoorn, Sven C. D., Arango, Diego
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.07.2015; Nature Publishing Group
• Subjects: 631/80/2023; 631/80/85/2361; 64/60; 82/51; Animal models; Animals; Atrophy; Cytomegalovirus; Diarrhea; Diarrhea - etiology; Diarrhea - pathology; Diarrhea - physiopathology; Disease Models, Animal; Embryos; Enterocytes; Female; Gestation; Humanities and Social Sciences; Inactivation; Inclusion bodies; Intestine; Malabsorption Syndromes - complications; Malabsorption Syndromes - pathology; Malabsorption Syndromes - physiopathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microvilli - pathology; Microvillus; Molecular modelling; Mucolipidoses - complications; Mucolipidoses - pathology; Mucolipidoses - physiopathology; multidisciplinary; Myosin Type V - genetics; Myosin Type V - metabolism; Nutrients; Rodents; Science
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep12312

Inherited MYO5B mutations have recently been associated with microvillus inclusion disease (MVID), an autosomal recessive syndrome characterized by intractable, life-threatening, watery diarrhea appearing shortly after birth. Characterization of the molecular mechanisms underlying this disease and development of novel therapeutic approaches is hampered by the lack of animal models. In this study we describe the phenotype of a novel mouse model with targeted inactivation of Myo5b . Myo5b knockout mice show perinatal mortality, diarrhea and the characteristic mislocalization of apical and basolateral plasma membrane markers in enterocytes. Moreover, in transmission electron preparations, we observed microvillus atrophy and the presence of microvillus inclusion bodies. Importantly, Myo5b knockout embryos at day 20 of gestation already display all these structural defects, indicating that they are tissue autonomous rather than secondary to environmental cues, such as the long-term absence of nutrients in the intestine. Myo5b knockout mice closely resemble the phenotype of MVID patients and constitute a useful model to further investigate the underlying molecular mechanism of this disease and to preclinically assess the efficacy of novel therapeutic approaches.