Human cytomegalovirus infection is associated with increased expression of the lissencephaly gene PAFAH1B1 encoding LIS1 in neural stem cells and congenitally infected brains
[en] Congenital infection of the central nervous system by human cytomegalovirus (HCMV) is a leading cause of permanent sequelae, including mental retardation or neurodevelopmental abnormalities. The most severe complications include smooth brain or polymicrogyria, which are both indicative of abnormal migration of neural cells, although the underlying mechanisms remain to be determined. To gain better insight on the pathogenesis of such sequelae, we assessed the expression levels of a set of neurogenesis-related genes, using HCMV-infected human neural stem cells derived from embryonic stem cells (NSCs). Among the 84 genes tested, we found dramatically increased expression of the gene PAFAH1B1, encoding LIS1 (lissencephaly-1), in HCMV-infected versus uninfected NSCs. Consistent with these ndings, western blotting and immunouorescence analyses conrmed the increased levels of LIS1 in HCMV-infected NSCs at the protein level. We next assessed the migratory abilities
of HCMV-infected NSCs and observed that infection strongly impaired the migration of NSCs, without detectable effect on their proliferation. Moreover, we observed increased immunostaining for LIS1 in brains of congenitally infected fetuses, but not in control samples, highlighting the clinical relevance of our ndings. Of note, PAFAH1B1 mutations (resulting in either haploinsufciency or gain of function) are primary causes of hereditary neurodevelopmental diseases. Notably, mutations resulting in PAFAH1B1 haploinsufciency cause classic lissencephaly. Taken together, our ndings suggest that PAFAH1B1 is a critical target of HCMV infection. They also shine a new light on the pathophysiological basis of the neurological outcomes of congenital HCMV infection, by suggesting that defective neural cell migration might contribute to the pathogenesis of the neurodevelopmental sequelae of infection
Research Center/Unit :
Centre for Pathophysiology Toulouse-Purpan (CPTP), INSERM, CNRS, University of Toulouse, Toulouse, France; Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France ; Université Paris Descartes, Paris, France ; Département d’Anatomie Pathologique, IUCT-Oncopôle Toulouse, Toulouse, France CECS, I-STEM, AFM, Corbeil-Essonnes, France
Disciplines :
Immunology & infectious disease
Author, co-author :
Rolland, Maude ; Centre for Pathophysiology Toulouse-Purpan (CPTP), INSERM, CNRS, University of Toulouse, Toulouse, France
MARTIN, HELENE; Centre for Pathophysiology Toulouse-Purpan (CPTP), INSERM, CNRS, University of Toulouse, Toulouse, France
BERGAMELLI, MATHILDE; Centre for Pathophysiology Toulouse-Purpan (CPTP), INSERM, CNRS, University of Toulouse, Toulouse, France
SELLIER, YANN; Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
BESSIERES, BETTINA; Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
AZIZA, JACQUELINE; Département d’Anatomie Pathologique, IUCT-Oncopôle Toulouse, Toulouse, France
BENCHOUA, ALEXANDRA; CECS, I-STEM, AFM, Corbeil-Essonnes, France
LERUEZ-VILLE, MARIANNE; Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
CHAVANAS, STEPHANE; Centre for Pathophysiology Toulouse-Purpan (CPTP), INSERM, CNRS, University of Toulouse, Toulouse, France
GONZALEZ-DUNIA, DANIEL; Centre for Pathophysiology Toulouse-Purpan (CPTP), INSERM, CNRS, University of Toulouse, Toulouse, France
Language :
English
Title :
Human cytomegalovirus infection is associated with increased expression of the lissencephaly gene PAFAH1B1 encoding LIS1 in neural stem cells and congenitally infected brains
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