β-Catenin Deletion in Regional Neural Progenitors Leads to Congenital Hydrocephalus in Mice
Lin Ma1,4,6,7 • Yanhua Du8 • Xiangjie Xu1,4,6 • Hexi Feng1,4,6 • Yi Hui1,4,6 • Nan Li1,4,6 • Guanyu Jiang4 • Xiaoqing Zhang1,2,3,5,6 • Xiaocui Li9 • Ling Liu1,4,6,7
1 Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China
2 Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of the Ministry of Education, Orthopaedic Department of Tongji Hospital, Shanghai 200065, China
3 Brain and Spinal Cord Innovative Research Center, School of Medicine, Tongji University, Shanghai 200092, China
4 Key Laboratory of Neuroregeneration of Shanghai Universities, School of Medicine, Tongji University, Shanghai 200092, China
5 Tsingtao Advanced Research Institute, Tongji University, Qingdao 266071, China
6 Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, China
7 Department of Pathology and Pathophysiology, School of Medicine, Tongji University, Shanghai 200092, China
8 Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
9 Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China
Abstract
Congenital hydrocephalus is a major neurological disorder with high rates of morbidity and mortality; however, the underlying cellular and molecular mechanisms remain largely unknown. Reproducible animal models mirroring both embryonic and postnatal hydrocephalus are also limited. Here, we describe a new mouse model of congenital hydrocephalus through knockout of bcatenin in Nkx2.1-expressing regional neural progenitors. Progressive ventriculomegaly and an enlarged brain were consistently observed in knockout mice from embryonic day 12.5 through to adulthood. Transcriptome profiling revealed severe dysfunctions in progenitor maintenance in the ventricular zone and therefore in cilium biogenesis after b-catenin knockout. Histological analyses also revealed an aberrant neuronal layout in both the ventral and dorsal telencephalon in hydrocephalic mice at both embryonic and postnatal stages. Thus, knockout of b-catenin in regional neural progenitors leads to congenital hydrocephalus and provides a reproducible animal model for studying pathological changes and developing therapeutic interventions for this devastating disease.
Keywords
Congenital hydrocephalus; b-Catenin;Ependymal cells; Nkx2.1; Neural development
