title: Lhx8 mediated Wnt and TGFβ pathways in tooth development and regeneration.
abstract: LIM homeobox 8 (Lhx8) is a highly conserved transcriptional factor with recently illustrated roles in cholinergic and GABAergic differentiation, and is expressed in neural crest derived craniofacial tissues during development. However, Lhx8 functions and signaling pathways are largely elusive. Here we showed that Lhx8 regulates dental mesenchyme differentiation and function via Wnt and TGFβ pathways. Lhx8 expression was restricted to dental mesenchyme from E11.5 to a peak at E14.5, and absent in dental epithelium. By reconstituting dental epithelium and mesenchyme in an E16.5 tooth organ, Lhx8 knockdown accelerated dental mesenchyme differentiation; conversely, Lhx8 overexpression attenuated dentin formation. Lhx8 overexpressed adult human dental pulp stem/progenitor cells in β-tricalcium phosphate cubes attenuated mineralized matrix production in vivo. Gene profiling revealed that postnatal dental pulp stem/progenitor cells upon Lhx8 overexpression modified matrix related gene expression including Dspp, Cola1 and osteocalcin. Lhx8 transcriptionally activated Wnt and TGFβ pathways, and its attenuation upregulated multiple dentinogenesis genes. Together, Lhx8 regulates dentin development and regeneration by fine-turning Wnt and TGFβ signaling.
authors.affiliation: Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, 56 Lingyuanxi Road, Guangzhou 510055, China; Center for Craniofacial Regeneration, Columbia University Medical Center, 630 W. 168 St. - PH7E - CDM, New York, NY 10032, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, 56 Lingyuanxi Road, Guangzhou 510055, China.
authors.forename: Guodong
authors.initials: G
authors.lastname: Yang
authors.affiliation: Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, 56 Lingyuanxi Road, Guangzhou 510055, China.
authors.forename: Mo
authors.initials: M
authors.lastname: Chen
authors.affiliation: Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, 56 Lingyuanxi Road, Guangzhou 510055, China.
authors.forename: Chenglin
authors.initials: C
authors.lastname: Wang
authors.affiliation: Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, 56 Lingyuanxi Road, Guangzhou 510055, China; Center for Craniofacial Regeneration, Columbia University Medical Center, 630 W. 168 St. - PH7E - CDM, New York, NY 10032, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: He
authors.affiliation: Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, 56 Lingyuanxi Road, Guangzhou 510055, China; Center for Craniofacial Regeneration, Columbia University Medical Center, 630 W. 168 St. - PH7E - CDM, New York, NY 10032, USA.
authors.forename: Lusai
authors.initials: L
authors.lastname: Xiang
authors.affiliation: Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, 56 Lingyuanxi Road, Guangzhou 510055, China.
authors.forename: Danying
authors.initials: D
authors.lastname: Chen
authors.affiliation: Center for Craniofacial Regeneration, Columbia University Medical Center, 630 W. 168 St. - PH7E - CDM, New York, NY 10032, USA. Electronic address: lingjq@mail.sysu.edu.cn.
authors.forename: Junqi
authors.initials: J
authors.lastname: Ling
authors.affiliation: Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, 56 Lingyuanxi Road, Guangzhou 510055, China. Electronic address: jmao@columbia.edu.
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Mao
mesh_terms: D000328:Adult; D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D000818:Animals; D002130:Calcium Phosphates / Q000737:chemistry; D002454:Cell Differentiation; D002478:Cells, Cultured; D003782:Dental Pulp / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D003810:Dentinogenesis; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009805:Odontogenesis; D012038:Regeneration; D015398:Signal Transduction; D054457:Tissue Scaffolds / Q000737:chemistry; D014070:Tooth / Q000166:cytology / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D002130:Calcium Phosphates; C112960:LIM homeobox protein 8; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; C485817:beta-tricalcium phosphate
keywords: Dentinogenesis; Lhx8; Signal pathways; Tooth regeneration; Transcriptional regulation