单位：[1]Department of Orthodontics, Affiliated Hospital of Stomatology, Medical College, Zhejiang University, Hangzhou, Zhejiang, PR China [2]Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, CA, USA [3]Department of Oral Implantology, Affiliated Hospital of Stomatology, Medical College, Zhejiang University, Hangzhou, Zhejiang, PR China [4]Center of Stomatology, China-Japan Friendship Hospital, 2nd Yinghuayuan East Street, Chaoyang District, Beijing, PR China[5]Department of Orthodontics, School and Hospital of Stomatology, Jilin University, Changchun, Jilin, PR China [6]Department of Cleft Lip and Palate Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, PR China [7]Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, UCLA and Orthopaedic Hospital, University of California, Los Angeles, CA, USA [8]UCLA Division of Plastic and Reconstructive Surgery and Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, University of California, Los Angeles, CA, USA
Upregulation of Nell-1 has been associated with craniosynostosis (CS) in humans, and validated in a mouse transgenic Nell-1 overexpression model. Global Nell-1 inactivation in mice by N-ethyl-N-nitrosourea (ENU) mutagenesis results in neonatal lethality with skeletal abnormalities including cleidocranial dysplasia (CCD)-like calvarial bone defects. This study further defines the role of Nell-1 in craniofacial skeletogenesis by investigating specific inactivation of Nell-1 in Wnt1 expressing cell lineages due to the importance of cranial neural crest cells (CNCCs) in craniofacial tissue development. Nell-1(flox/flox); Wnt1-Cre (Nell-1(Wnt1) KO) mice were generated for comprehensive analysis, while the relevant reporter mice were created for CNCC lineage tracing. Nell-1(Wnt1) KO mice were born alive, but revealed significant frontonasal and mandibular bone defects with complete penetrance. Immunostaining demonstrated that the affected craniofacial bones exhibited decreased osteogenic and Wnt/beta-catenin markers (Osteocalcin and active-beta-catenin). Nell-1-deficient CNCCs demonstrated a significant reduction in cell proliferation and osteogenic differentiation. Active-beta-catenin levels were significantly low in Nell-1-deficient CNCCs, but were rescued along with osteogenic capacity to a level close to that of wild-type (WT) cells via exogenous Nell-1 protein. Surprisingly, 5.4% of young adult Nell-1(Wnt1) KO mice developed hydrocephalus with premature ossification of the intrasphenoidal synchondrosis and widened frontal, sagittal, and coronal sutures. Furthermore, the epithelial cells of the choroid plexus and ependymal cells exhibited degenerative changes with misplaced expression of their respective markers, transthyretin and vimentin, as well as dysregulated Pit-2 expression in hydrocephalic Nell-1(Wnt1) KO mice. Nell-1(Wnt1) KO embryos at E9.5, 14.5, 17.5, and newborn mice did not exhibit hydrocephalic phenotypes grossly and/or histologically. Collectively, Nell-1 is a pivotal modulator of CNCCs that is essential for normal development and growth of the cranial vault and base, and mandibles partially via activating the Wnt/beta-catenin pathway. Nell-1 may also be critically involved in regulating cerebrospinal fluid homeostasis and in the pathogenesis of postnatal hydrocephalus.
基金：
NIH-NIAMSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) [R01AR066782, R01AR068835, R01AR061399]; NIH-NIDCRUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Dental & Craniofacial Research (NIDCR) [K08DE026805]; UCLA/NIH CTSI [UL1TR000124]; National Aeronautical and Space Administration (NASA)National Aeronautics & Space Administration (NASA) [GA-2014-154]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81670972, 81400538]; Zhejiang Provincial Natural Science Foundation of ChinaNatural Science Foundation of Zhejiang Province [LY19H140002]
第一作者单位：[1]Department of Orthodontics, Affiliated Hospital of Stomatology, Medical College, Zhejiang University, Hangzhou, Zhejiang, PR China [2]Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, CA, USA
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通讯作者：
推荐引用方式(GB/T 7714)：
Xiaoyan Chen,Huiming Wang,Mengliu Yu,et al.Cumulative inactivation of Nell-1 in Wnt1 expressing cell lineages results in craniofacial skeletal hypoplasia and postnatal hydrocephalus[J].CELL DEATH and DIFFERENTIATION.2020,27(4):1415-1430.doi:10.1038/s41418-019-0427-1.
APA：
Xiaoyan Chen,Huiming Wang,Mengliu Yu,Jong Kil Kim,Huichuan Qi...&Chia Soo.(2020).Cumulative inactivation of Nell-1 in Wnt1 expressing cell lineages results in craniofacial skeletal hypoplasia and postnatal hydrocephalus.CELL DEATH and DIFFERENTIATION,27,(4)
MLA：
Xiaoyan Chen,et al."Cumulative inactivation of Nell-1 in Wnt1 expressing cell lineages results in craniofacial skeletal hypoplasia and postnatal hydrocephalus".CELL DEATH and DIFFERENTIATION 27..4(2020):1415-1430
生物