Craniofacial microsomia(CFM)is a congenital malformation with maxillary and/or mandibular hypoplasia,skin tags,and ear malformations(Luo et al.,2023).Microtia,in its mildest form,can occur alone(Quiat et al.,2023).Wit...Craniofacial microsomia(CFM)is a congenital malformation with maxillary and/or mandibular hypoplasia,skin tags,and ear malformations(Luo et al.,2023).Microtia,in its mildest form,can occur alone(Quiat et al.,2023).With a prevalence of 3.8/100,000(Barisic et al.,2014),CFM is the second most common congenital craniofacial abnormality(Li et al.,2022;Luo et al.,2023).Most cases are sporadic,but familial ones suggest autosomal dominant(AD)or autosomal recessive(AR)(Beleza-Meireles et al.,2014).In 2023,Quiat et al.and Mao et al.successively identified FOXI3 variants in 16 pedigrees and 10 sporadic cases,respectively,accounting for 3.1%of CFM cases(Mao et al.,2023;Quiat et al.,2023).FOX/3 has surpassed SF3B2 as the most frequently identified pathogenic gene for CFM to date(Timberlake et al.,2021;Mao et al.,2023;Quiat et al.,2023).In this study,we performed whole-exome sequencing(WES)on 201 CFM pedigrees and detected FOX/3 variants in 8 AD-inherited pedigrees with 24 patients and 28 unaffected individuals(Fig.1A).展开更多
Craniofacial development relies on the migration of cranial neural crest cells(CNCCs)to the first and second pharyngeal arches,followed by their differentiation into various cell types during embryogenesis.Although th...Craniofacial development relies on the migration of cranial neural crest cells(CNCCs)to the first and second pharyngeal arches,followed by their differentiation into various cell types during embryogenesis.Although the CNCC migration has been well-studied,the role of the niche in relation to CNCC remains unclear.Variants in FOXI3 have been implicated in craniofacial microsomia(CFM),yet the molecular mechanisms remain unexplored.FOXI3 is expressed in the ectoderm and auricle epidermis,but not in CNCCs or cartilage.Deletion of Foxi3 in the mouse CNCCs did not disrupt mandible and auricular development,further confirming that FOXI3 does not directly regulate CNCCs.However,Foxi3 deficiency in the ectoderm reduced the production of chondrogenesis-related cytokines derived from ectodermal cells,such as TGF-β1.This impairment affected CNCC proliferation through cell communication,subsequently altering the development of the mandible and auricle.These results emphasize the critical role of FOXI3 in establishing the microenvironment supporting CNCC function.Furthermore,FOXI3 directly regulates target genes associated with translation,thereby orchestrating cytokine production in epidermal cells.The validation using auricle sample from a CFM patient carrying FOXI3 mutation further supports our findings.These insights highlight the function of FOXI3 in creating the niche necessary for CNCC development and provide a basis for understanding the molecular mechanisms driving CFM pathogenesis.展开更多
基金support in this study.This work was supported by the National Natural Science Foundation of China(82271889,82172105)the National Key Research and Development Program of China(2021YFC2701000)Shanghai Natural Science Foundation(23ZR1409400,24ZR1409400).
文摘Craniofacial microsomia(CFM)is a congenital malformation with maxillary and/or mandibular hypoplasia,skin tags,and ear malformations(Luo et al.,2023).Microtia,in its mildest form,can occur alone(Quiat et al.,2023).With a prevalence of 3.8/100,000(Barisic et al.,2014),CFM is the second most common congenital craniofacial abnormality(Li et al.,2022;Luo et al.,2023).Most cases are sporadic,but familial ones suggest autosomal dominant(AD)or autosomal recessive(AR)(Beleza-Meireles et al.,2014).In 2023,Quiat et al.and Mao et al.successively identified FOXI3 variants in 16 pedigrees and 10 sporadic cases,respectively,accounting for 3.1%of CFM cases(Mao et al.,2023;Quiat et al.,2023).FOX/3 has surpassed SF3B2 as the most frequently identified pathogenic gene for CFM to date(Timberlake et al.,2021;Mao et al.,2023;Quiat et al.,2023).In this study,we performed whole-exome sequencing(WES)on 201 CFM pedigrees and detected FOX/3 variants in 8 AD-inherited pedigrees with 24 patients and 28 unaffected individuals(Fig.1A).
基金supported by the National Natural Science Foundation of China(No.82271889,82572117,82371173,82172105)the National Key Research and Development Program of China(No.2021YFC2701000)Shanghai Natural Science Foundation(23ZR1409400,24ZR1409400)。
文摘Craniofacial development relies on the migration of cranial neural crest cells(CNCCs)to the first and second pharyngeal arches,followed by their differentiation into various cell types during embryogenesis.Although the CNCC migration has been well-studied,the role of the niche in relation to CNCC remains unclear.Variants in FOXI3 have been implicated in craniofacial microsomia(CFM),yet the molecular mechanisms remain unexplored.FOXI3 is expressed in the ectoderm and auricle epidermis,but not in CNCCs or cartilage.Deletion of Foxi3 in the mouse CNCCs did not disrupt mandible and auricular development,further confirming that FOXI3 does not directly regulate CNCCs.However,Foxi3 deficiency in the ectoderm reduced the production of chondrogenesis-related cytokines derived from ectodermal cells,such as TGF-β1.This impairment affected CNCC proliferation through cell communication,subsequently altering the development of the mandible and auricle.These results emphasize the critical role of FOXI3 in establishing the microenvironment supporting CNCC function.Furthermore,FOXI3 directly regulates target genes associated with translation,thereby orchestrating cytokine production in epidermal cells.The validation using auricle sample from a CFM patient carrying FOXI3 mutation further supports our findings.These insights highlight the function of FOXI3 in creating the niche necessary for CNCC development and provide a basis for understanding the molecular mechanisms driving CFM pathogenesis.
