RESUMEN
Tendons and ligaments are fibrous connective tissues vital to the transmission of force and stabilization of the musculoskeletal system. Arising in precise regions of the embryo, tendons and ligaments share many properties and little is known about the molecular differences that differentiate them. Recent studies have revealed heterogeneity and plasticity within tendon and ligament cells, raising questions regarding the developmental mechanisms regulating tendon and ligament identity. Here, we discuss recent findings that contribute to our understanding of the mechanisms that establish and maintain tendon progenitors and their differentiated progeny in the head, trunk and limb. We also review the extent to which these findings are specific to certain anatomical regions and model organisms, and indicate which findings similarly apply to ligaments. Finally, we address current research regarding the cellular lineages that contribute to tendon and ligament repair, and to what extent their regulation is conserved within tendon and ligament development.
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Diferenciación Celular , Ligamentos/embriología , Desarrollo Musculoesquelético , Células Madre/metabolismo , Tendones/embriología , Animales , Humanos , Ligamentos/citología , Células Madre/citología , Tendones/citologíaRESUMEN
The Society for Craniofacial Genetics and Developmental Biology (SCGDB) held its 46th Annual Meeting at Cincinnati Children's Hospital Medical Center in Cincinnati, Ohio on October 10th-12th, 2023. On the first day of the meeting, Drs. Sally Moody and Justin Cotney were each honored with the SCGDB Distinguished Scientist Awards for their exceptional contributions to the field of craniofacial biology. The following two days of the meeting featured five sessions that highlighted new discoveries in signaling and genomic mechanisms regulating craniofacial development, human genetics, translational and regenerative approaches, and clinical management of craniofacial differences. Interactive workshops on spatial transcriptomics and scientific communication, as well as a poster session facilitated meaningful interactions among the 122 attendees representing diverse career stages and research backgrounds in developmental biology and genetics, strengthened the SCGDB community.
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Anomalías Craneofaciales , Biología Evolutiva , Humanos , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/patologíaRESUMEN
Fibroblast Growth Factor 2 (FGF2), also known as basic fibroblast growth factor, is a potent stimulator of growth and differentiation in multiple tissues. Its discovery traces back over 50 years ago when it was first isolated from bovine pituitary extracts due to its ability to stimulate fibroblast proliferation. Subsequent studies investigating the genomic structure of FGF2 identified multiple protein isoforms, categorized as the low molecular weight and high molecular weight FGF2. These isoforms arise from alternative translation initiation events and exhibit unique molecular and cellular functions. In this concise review, we aim to provide an overview of what is currently known about the structure, expression, and functions of the FGF2 isoforms within the contexts of development, homeostasis, and disease.
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The Society for Craniofacial Genetics and Developmental Biology (SCGDB) held its 45th Annual Meeting at the Sanford Consortium for Regenerative Medicine at the University of California, San Diego on October 20th-21st, 2022. The meeting included presentation of the SCGDB Distinguished Scientists in Craniofacial Research Awards to Drs. Ralph Marcucio and Loydie Jerome-Majewska and four scientific sessions that highlighted new discoveries in signaling in craniofacial development, genomics of craniofacial development, human genetics of craniofacial development and translational and regenerative approaches in craniofacial biology. The meeting also included workshops on analysis of single cell RNA sequencing datasets and using human sequencing data from the Gabriella Miller Kids First Pediatric Research Program. There were 110 faculty and trainees in attendance that represent a diverse group of researchers from all career stages in the fields of developmental biology and genetics. The meeting, which also included outdoor poster presentations, provided opportunities for participant interactions and discussions, thus strengthening the SCGDB community.
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Distinciones y Premios , Genómica , Niño , Humanos , Biología Evolutiva , Congresos como AsuntoRESUMEN
Tendon and bone are attached by a transitional connective tissue that is morphologically graded from tendinous to osseous and develops from bipotent progenitors that co-express scleraxis (Scx) and Sox9 (Scx+/Sox9+). Scx+/Sox9+ progenitors have the potential to differentiate into either tenocytes or chondrocytes, yet the developmental mechanism that spatially resolves their bipotency at the tendon-bone interface during embryogenesis remains unknown. Here, we demonstrate that development of Scx+/Sox9+ progenitors within the mammalian lower jaw requires FGF signaling. We find that loss of Fgfr2 in the mouse tendon-bone interface reduces Scx expression in Scx+/Sox9+ progenitors and induces their biased differentiation into Sox9+ chondrocytes. This expansion of Sox9+ chondrocytes, which is concomitant with decreased Notch2-Dll1 signaling, prevents formation of a mixed population of chondrocytes and tenocytes, and instead results in ectopic endochondral bone at tendon-bone attachment units. Our work shows that FGF signaling directs zonal patterning at the boundary between tendon and bone by regulating cell fate decisions through a mechanism that employs Notch signaling.
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Huesos/metabolismo , Condrocitos/citología , Factores de Crecimiento de Fibroblastos/metabolismo , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Tendones/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Huesos/citología , Diferenciación Celular/fisiología , Regulación del Desarrollo de la Expresión Génica/genética , Maxilares/metabolismo , Ratones , Ratones Noqueados , Factor de Transcripción SOX9/metabolismo , Transducción de Señal/fisiología , Células Madre/fisiología , Tendones/citología , Tenocitos/citologíaRESUMEN
The Society for Craniofacial Genetics and Developmental Biology (SCGDB) held its 44th Annual Meeting in a virtual format on October 18-19, 2021. The SCGDB meeting included presentation of the SCGDB Distinguished Scientists in Craniofacial Research Awards to Drs. Paul Trainor and Jeff Bush and four scientific sessions on the genomics of craniofacial development, craniofacial morphogenesis and regeneration, translational craniofacial biology and signaling during craniofacial development. The meeting also included workshops on professional development for faculty and trainees, National Institutes of Health (NIH)/National Institute of Craniofacial and Dental Research funding and usage of Genomics Software, as well as two poster sessions. An exhibitor booth run by FaceBase was also present to facilitate the upload and download of datasets relevant to the craniofacial community. Over 200 attendees from 12 countries and 23 states, representing over 80 different scientific institutions, participated. This diverse group of scientists included cell biologists, developmental biologists, and clinical geneticists. Although the continuing COVID-19 pandemic forced a virtual meeting format for a second year in a row, the meeting platform provided ample opportunities for participant interactions and discussions, thus strengthening the community.
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COVID-19 , Pandemias , Biología Evolutiva , Genómica , Humanos , Programas Informáticos , Estados UnidosRESUMEN
Ribosome biogenesis is a global process required for growth and proliferation in all cells, but disruptions in this process surprisingly lead to tissue-specific phenotypic disorders termed ribosomopathies. Pathogenic variants in the RNA Polymerase (Pol) I subunit POLR1A cause Acrofacial Dysostosis-Cincinnati type, which is characterized by craniofacial and limb anomalies. In a zebrafish model of Acrofacial Dysostosis-Cincinnati type, we demonstrate that polr1a-/- mutants exhibit deficient 47S rRNA transcription, reduced monosomes and polysomes and, consequently, defects in protein translation. This results in Tp53-dependent neuroepithelial apoptosis, diminished neural crest cell proliferation and cranioskeletal anomalies. This indicates that POLR1A is critical for rRNA transcription, which is considered a rate limiting step in ribosome biogenesis, underpinning its requirement for neuroepithelial cell and neural crest cell proliferation and survival. To understand the contribution of the Tp53 pathway to the pathogenesis of Acrofacial Dysostosis-Cincinnati type, we genetically inhibited tp53 in polr1a-/- mutant embryos. Tp53 inhibition suppresses neuroepithelial apoptosis and partially ameliorates the polr1a mutant phenotype. However, complete rescue of cartilage development is not observed due to the failure to improve rDNA transcription and neural crest cell proliferation. Altogether, these data reveal specific functions for both Tp53-dependent and independent signaling downstream of polr1a in ribosome biogenesis during neural crest cell and craniofacial development, in the pathogenesis of Acrofacial Dysostosis-Cincinnati type. Furthermore, our work sets the stage for identifying Tp53-independent therapies to potentially prevent Acrofacial dysostosis-Cincinnati type and other similar ribosomopathies.
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Deformidades Congénitas de las Extremidades/metabolismo , Disostosis Mandibulofacial/metabolismo , Cresta Neural/patología , Proteína p53 Supresora de Tumor/metabolismo , Proteínas de Pez Cebra/metabolismo , Animales , Diferenciación Celular/genética , Proliferación Celular/genética , Modelos Animales de Enfermedad , Embrión no Mamífero , Regulación del Desarrollo de la Expresión Génica , Humanos , Deformidades Congénitas de las Extremidades/patología , Disostosis Mandibulofacial/patología , Mutación , ARN Polimerasa I/genética , ARN Polimerasa I/metabolismo , Transducción de Señal , Proteína p53 Supresora de Tumor/genética , Pez Cebra/embriología , Pez Cebra/genética , Proteínas de Pez Cebra/genéticaRESUMEN
BACKGROUND: Bent bone dysplasia syndrome (BBDS), a congenital skeletal disorder caused by dominant mutations in fibroblast growth factor receptor 2 (FGFR2), is characterized by bowed long bones within the limbs. We previously showed that the FGFR2 mutations in BBDS enhance nuclear and nucleolar localization of the receptor; however, exactly how shifts in subcellular distribution of FGFR2 affect limb development remained unknown. RESULTS: Targeted expression of the BBDS mutations in the lateral plate mesoderm of the developing chick induced angulated hindlimbs, a hallmark feature of the disease. Whole-mount analysis of the underlying skeleton revealed bent long bones with shortened bone collars and, in severe cases, dysmorphic epiphyses. Epiphyseal changes were also correlated with joint dislocations and contractures. Histological analysis revealed that bent long bones and joint defects were closely associated with irregularities in skeletal muscle patterning and tendon-to-bone attachment. The spectrum of limb phenotypes induced by the BBDS mutations were recapitulated by targeted expression of wild-type FGFR2 appended with nuclear and nucleolar localization signals. CONCLUSIONS: Our results indicate that the bent long bones in BBDS arise from disruptions in musculoskeletal integration and that increased nuclear and nucleolar localization of FGFR2 plays a mechanistic role in the disease phenotype. 248:233-246, 2019. © 2018 Wiley Periodicals, Inc.
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Núcleo Celular/química , Extremidades/crecimiento & desarrollo , Proteínas Tirosina Quinasas Receptoras/genética , Receptores de Factores de Crecimiento de Fibroblastos/genética , Animales , Enfermedades del Desarrollo Óseo/genética , Embrión de Pollo , Deformidades Congénitas de las Extremidades/genética , Fenotipo , Proteínas Tirosina Quinasas Receptoras/fisiología , Receptores de Factores de Crecimiento de Fibroblastos/fisiologíaRESUMEN
The skeletal structure of the mammalian middle ear, which is composed of three endochondral ossicles suspended within a membranous air-filled capsule, plays a critical role in conducting sound. Gene mutations that alter skeletal development in the middle ear result in auditory impairment. Mutations in fibroblast growth factor receptor 2 (FGFR2), an important regulator of endochondral and intramembranous bone formation, cause a spectrum of congenital skeletal disorders featuring conductive hearing loss. Although the middle ear malformations in multiple FGFR2 gain-of-function disorders are clinically characterized, those in the FGFR2 loss-of-function disorder lacrimo-auriculo-dento-digital (LADD) syndrome are relatively undescribed. To better understand conductive hearing loss in LADD, we examined the middle ear skeleton of mice with conditional loss of Fgfr2. We find that decreased auditory function in Fgfr2 mutant mice correlates with hypoplasia of the auditory bulla and ectopic bone growth at sites of tendon/ligament attachment. We show that ectopic bone associated with the intra-articular ligaments of the incudomalleal joint is derived from Scx-expressing cells and preceded by decreased expression of the joint progenitor marker Gdf5. Together, these results identify a role for Fgfr2 in development of the middle ear skeletal tissues and suggest potential causes for conductive hearing loss in LADD syndrome.
Asunto(s)
Anomalías Múltiples/genética , Oído Medio/metabolismo , Pérdida Auditiva/genética , Enfermedades del Aparato Lagrimal/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismo , Sindactilia/genética , Anomalías Dentarias/genética , Animales , Desarrollo Óseo , Oído Medio/anomalías , Oído Medio/embriología , Factor 5 de Diferenciación de Crecimiento/metabolismo , Mutación con Pérdida de Función , Ratones , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genéticaRESUMEN
Fibroblast Growth Factor (FGF) signaling promotes self-renewal in progenitor cells by encouraging proliferation and inhibiting cellular senescence. Yet, these beneficial effects can be hijacked by disease-causing mutations in FGF receptor (FGFR) during embryogenesis. By studying dominant FGFR2 mutations that are germline in bent bone dysplasia syndrome (BBDS), we reveal a mechanistic connection between FGFR2, ribosome biogenesis, and cellular stress that links cell fate determination to disease pathology. We previously showed that FGFR2 mutations in BBDS, which amplify nucleolar targeting of FGFR2, activate ribosomal DNA (rDNA) transcription and delay differentiation in osteoprogenitor cells and patient-derived bone. Here we find that the BBDS mutations augment the ability of FGFR2 to recruit histone-remodeling factors that epigenetically activate transcriptionally silent rDNA. Nucleolar morphology is controlled by chromatin structure, and the high levels of euchromatic rDNA induced by the BBDS mutations direct nucleolar disorganization, alter ribosome biogenesis, and activate the Rpl11-Mdm2-p53 nucleolar stress response pathway. Inhibition of p53 in cells expressing the FGFR2 mutations in BBDS rescues delayed osteoblast differentiation, suggesting that p53 activation is an essential pathogenic factor in, and potential therapeutic target for, BBDS. This work establishes rDNA as developmentally regulated loci that receive direct input from FGF signaling to balance self-renewal and cell fate determination.
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Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismo , Enfermedades del Desarrollo Óseo/genética , Enfermedades del Desarrollo Óseo/metabolismo , Diferenciación Celular/fisiología , Proliferación Celular/genética , Proliferación Celular/fisiología , ADN Ribosómico/metabolismo , Humanos , Mutación , Osteoblastos/metabolismo , Osteogénesis/genética , Fragmentos de Péptidos/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Ribosomas/metabolismo , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
PURPOSE OF REVIEW: Fibroblast growth factor receptor (FGFR) signaling regulates proliferation and differentiation during development and homeostasis. While membrane-bound FGFRs play a central role in these processes, the function of nuclear FGFRs is also critical. Here, we highlight mechanisms for nuclear FGFR translocation and the effects of nuclear FGFRs on skeletal development and disease. RECENT FINDINGS: Full-length FGFRs, internalized by endocytosis, enter the nucleus through ß-importin-dependent mechanisms that recognize the nuclear localization signal within FGFs. Alternatively, soluble FGFR intracellular fragments undergo nuclear translocation following their proteolytic release from the membrane. FGFRs enter the nucleus during the cellular transition between proliferation and differentiation. Once nuclear, FGFRs interact with chromatin remodelers to alter the epigenetic state and transcription of their target genes. Dysregulation of nuclear FGFR is linked to the etiology of congenital skeletal disorders and neoplastic transformation. Revealing the activities of nuclear FGFR will advance our understanding of 20 congenital skeletal disorders caused by FGFR mutations, as well as FGFR-related cancers.
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Enfermedades Óseas/etiología , Factores de Crecimiento de Fibroblastos/fisiología , Osteogénesis/fisiología , Receptores de Factores de Crecimiento de Fibroblastos/fisiología , Diferenciación Celular , Humanos , Transducción de SeñalRESUMEN
Ribosome biogenesis is a global process required for growth and proliferation of all cells, yet perturbation of ribosome biogenesis during human development often leads to tissue-specific defects termed ribosomopathies. Transcription of the ribosomal RNAs (rRNAs) by RNA polymerases (Pol) I and III, is considered a rate limiting step of ribosome biogenesis and mutations in the genes coding for RNA Pol I and III subunits, POLR1C and POLR1D cause Treacher Collins syndrome, a rare congenital craniofacial disorder. Our understanding of the functions of individual RNA polymerase subunits, however, remains poor. We discovered that polr1c and polr1d are dynamically expressed during zebrafish embryonic development, particularly in craniofacial tissues. Consistent with this pattern of activity, polr1c and polr1d homozygous mutant zebrafish exhibit cartilage hypoplasia and cranioskeletal anomalies characteristic of humans with Treacher Collins syndrome. Mechanistically, we discovered that polr1c and polr1d loss-of-function results in deficient ribosome biogenesis, Tp53-dependent neuroepithelial cell death and a deficiency of migrating neural crest cells, which are the primary progenitors of the craniofacial skeleton. More importantly, we show that genetic inhibition of tp53 can suppress neuroepithelial cell death and ameliorate the skeletal anomalies in polr1c and polr1d mutants, providing a potential avenue to prevent the pathogenesis of Treacher Collins syndrome. Our work therefore has uncovered tissue-specific roles for polr1c and polr1d in rRNA transcription, ribosome biogenesis, and neural crest and craniofacial development during embryogenesis. Furthermore, we have established polr1c and polr1d mutant zebrafish as models of Treacher Collins syndrome together with a unifying mechanism underlying its pathogenesis and possible prevention.
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Anomalías Craneofaciales/genética , ARN Polimerasas Dirigidas por ADN/genética , Disostosis Mandibulofacial/genética , Cresta Neural/crecimiento & desarrollo , Animales , Diferenciación Celular/genética , Anomalías Craneofaciales/fisiopatología , ARN Polimerasas Dirigidas por ADN/biosíntesis , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/fisiopatología , Modelos Animales de Enfermedad , Desarrollo Embrionario/genética , Humanos , Disostosis Mandibulofacial/fisiopatología , Mutación , Proteína p53 Supresora de Tumor/genética , Pez Cebra/genética , Pez Cebra/crecimiento & desarrolloRESUMEN
Spondylocarpotarsal synostosis (SCT) is an autosomal recessive disorder characterized by progressive vertebral fusions and caused by loss of function mutations in Filamin B (FLNB). FLNB acts as a signaling scaffold by linking the actin cytoskleteon to signal transduction systems, yet the disease mechanisms for SCT remain unclear. Employing a Flnb knockout mouse, we found morphologic and molecular evidence that the intervertebral discs (IVDs) of Flnb-/-mice undergo rapid and progressive degeneration during postnatal development as a result of abnormal cell fate changes in the IVD, particularly the annulus fibrosus (AF). In Flnb-/-mice, the AF cells lose their typical fibroblast-like characteristics and acquire the molecular and phenotypic signature of hypertrophic chondrocytes. This change is characterized by hallmarks of endochondral-like ossification including alterations in collagen matrix, expression of Collagen X, increased apoptosis, and inappropriate ossification of the disc tissue. We show that conversion of the AF cells into chondrocytes is coincident with upregulated TGFß signaling via Smad2/3 and BMP induced p38 signaling as well as sustained activation of canonical and noncanonical target genes p21 and Ctgf. These findings indicate that FLNB is involved in attenuation of TGFß/BMP signaling and influences AF cell fate. Furthermore, we demonstrate that the IVD disruptions in Flnb-/-mice resemble aging degenerative discs and reveal new insights into the molecular causes of vertebral fusions and disc degeneration.
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Anomalías Múltiples/genética , Filaminas/genética , Degeneración del Disco Intervertebral/genética , Vértebras Lumbares/anomalías , Enfermedades Musculoesqueléticas/genética , Escoliosis/congénito , Sinostosis/genética , Vértebras Torácicas/anomalías , Factor de Crecimiento Transformador beta/genética , Anomalías Múltiples/patología , Citoesqueleto de Actina/genética , Citoesqueleto de Actina/metabolismo , Animales , Proteínas Morfogenéticas Óseas/genética , Proteínas Morfogenéticas Óseas/metabolismo , Condrocitos/metabolismo , Condrocitos/patología , Factor de Crecimiento del Tejido Conjuntivo/genética , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Modelos Animales de Enfermedad , Placa de Crecimiento/crecimiento & desarrollo , Placa de Crecimiento/patología , Humanos , Degeneración del Disco Intervertebral/patología , Vértebras Lumbares/patología , Ratones , Ratones Noqueados , Enfermedades Musculoesqueléticas/patología , Escoliosis/genética , Escoliosis/patología , Transducción de Señal , Proteínas Smad/genética , Proteínas Smad/metabolismo , Columna Vertebral/crecimiento & desarrollo , Columna Vertebral/patología , Sinostosis/patología , Vértebras Torácicas/patologíaRESUMEN
Craniofacial development is an intricate process of patterning, morphogenesis, and growth that involves many tissues within the developing embryo. Genetic misregulation of these processes leads to craniofacial malformations, which comprise over one-third of all congenital birth defects. Significant advances have been made in the clinical management of craniofacial disorders, but currently very few treatments specifically target the underlying molecular causes. Here, we review recent studies in which modeling of craniofacial disorders in primary patient cells, patient-derived induced pluripotent stem cells (iPSCs), and mice have enhanced our understanding of the etiology and pathophysiology of these disorders while also advancing therapeutic avenues for their prevention.
RESUMEN
Here we review studies identifying regulatory networks responsible for synovial, cartilaginous, and fibrous joint development. Synovial joints, characterized by the fluid-filled synovial space between the bones, are found in high-mobility regions and are the most common type of joint. Cartilaginous joints such as the intervertebral disc unite adjacent bones through either a hyaline cartilage or a fibrocartilage intermediate. Fibrous joints, which include the cranial sutures, form a direct union between bones through fibrous connective tissue. We describe how the distinct morphologic and histogenic characteristics of these joint classes are established during embryonic development. Collectively, these studies reveal that despite the heterogeneity of joint strength and mobility, joint development throughout the skeleton utilizes common signaling networks via long-range morphogen gradients and direct cell-cell contact. This suggests that different joint types represent specialized variants of homologous developmental modules. Identifying the unifying aspects of the signaling networks between joint classes allows a more complete understanding of the signaling code for joint formation, which is critical to improving strategies for joint regeneration and repair. Developmental Dynamics 246:262-274, 2017. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Articulaciones/crecimiento & desarrollo , Transducción de Señal/fisiología , Animales , Cartílago Articular , Redes Reguladoras de Genes , Humanos , Cápsula Articular , Articulaciones/anatomía & histología , Articulaciones/embriología , Morfogénesis , RegeneraciónRESUMEN
Fibroblast growth factor receptor 2 (FGFR2) promotes osteoprogenitor proliferation and differentiation during bone development, yet how the receptor elicits these distinct cellular responses remains unclear. Analysis of the FGFR2-skeletal disorder bent bone dysplasia syndrome (BBDS) demonstrates that FGFR2, in addition to its canonical signaling activities at the plasma membrane, regulates bone formation from within the nucleolus. Previously, we showed that the unique FGFR2 mutations that cause BBDS reduce receptor levels at the plasma membrane and diminish responsiveness to extracellular FGF2. In this study, we find that these mutations, despite reducing canonical signaling, enhance nucleolar occupancy of FGFR2 at the ribosomal DNA (rDNA) promoter. Nucleolar FGFR2 activates rDNA transcription via interactions with FGF2 and UBF1 by de-repressing RUNX2. An increase in the nucleolar activity of FGFR2 in BBDS elevates levels of ribosomal RNA in the developing bone, consequently promoting osteoprogenitor cell proliferation and decreasing differentiation. Identifying FGFR2 as a transcriptional regulator of rDNA in bone unexpectedly reveals a nucleolar route for FGF signaling that allows for independent regulation of osteoprogenitor cell proliferation and differentiation.
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Acrocefalosindactilia/genética , Acrocefalosindactilia/metabolismo , Núcleo Celular/metabolismo , ADN Ribosómico/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismo , Transcripción Genética , Animales , Sitios de Unión , Diferenciación Celular , Línea Celular , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Regulación de la Expresión Génica , Humanos , Sistema de Señalización de MAP Quinasas , Ratones , Mutación , Osteoblastos/citología , Osteoblastos/metabolismo , Proteínas del Complejo de Iniciación de Transcripción Pol1/metabolismo , Unión Proteica , Transporte de Proteínas , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Secuencias Repetitivas de Ácidos NucleicosRESUMEN
Bent Bone Dysplasia-FGFR2 type is a relatively recently described bent bone phenotype with diagnostic clinical, radiographic, and molecular characteristics. Here we report on 11 individuals, including the original four patients plus seven new individuals with three longer-term survivors. The prenatal phenotype included stillbirth, bending of the femora, and a high incidence of polyhydramnios, prematurity, and perinatal death in three of 11 patients in the series. The survivors presented with characteristic radiographic findings that were observed among those with lethality, including bent bones, distinctive (moustache-shaped) small clavicles, angel-shaped metacarpals and phalanges, poor mineralization of the calvarium, and craniosynostosis. Craniofacial abnormalities, hirsutism, hepatic abnormalities, and genitourinary abnormalities were noted as well. Longer-term survivors all needed ventilator support. Heterozygosity for mutations in the gene that encodes Fibroblast Growth Factor Receptor 2 (FGFR2) was identified in the nine individuals with available DNA. Description of these patients expands the prenatal and postnatal findings of Bent Bone Dysplasia-FGFR2 type and adds to the phenotypic spectrum among all FGFR2 disorders. © 2016 Wiley Periodicals, Inc.
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Clavícula/anomalías , Falanges de los Dedos de la Mano/anomalías , Mutación , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Fenotipo , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Alelos , Sustitución de Aminoácidos , Facies , Femenino , Genotipo , Humanos , Masculino , Embarazo , Resultado del Embarazo , Diagnóstico Prenatal , Radiografía , Sistema de RegistrosRESUMEN
The skeleton affords a framework and structural support for vertebrates, while also facilitating movement, protecting vital organs, and providing a reservoir of minerals and cells for immune system and vascular homeostasis. The mechanical and biological functions of the skeleton are inextricably linked to the size and shape of individual bones, the diversity of which is dependent in part upon differential growth and proliferation. Perturbation of bone development, growth and proliferation, can result in congenital skeletal anomalies, which affect approximately 1 in 3000 live births [1]. Ribosome biogenesis is integral to all cell growth and proliferation through its roles in translating mRNAs and building proteins. Disruption of any steps in the process of ribosome biogenesis can lead to congenital disorders termed ribosomopathies. In this review, we discuss the role of ribosome biogenesis in skeletal development and in the pathogenesis of congenital skeletal anomalies. This article is part of a Special Issue entitled: Role of the Nucleolus in Human Disease.
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Desarrollo Óseo/genética , Enfermedades del Desarrollo Óseo/genética , Ribosomas/metabolismo , Esqueleto , Anemia de Diamond-Blackfan/genética , Anemia de Diamond-Blackfan/patología , Enfermedades del Desarrollo Óseo/metabolismo , Enfermedades del Desarrollo Óseo/fisiopatología , Enfermedades de la Médula Ósea/genética , Enfermedades de la Médula Ósea/patología , Insuficiencia Pancreática Exocrina/genética , Insuficiencia Pancreática Exocrina/patología , Cabello/anomalías , Cabello/patología , Enfermedad de Hirschsprung/genética , Enfermedad de Hirschsprung/patología , Humanos , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/patología , Lipomatosis/genética , Lipomatosis/patología , Disostosis Mandibulofacial/genética , Disostosis Mandibulofacial/patología , Osteocondrodisplasias/congénito , Osteocondrodisplasias/genética , Osteocondrodisplasias/patología , Enfermedades de Inmunodeficiencia Primaria , ARN Mensajero/genética , Ribosomas/genética , Síndrome de Shwachman-DiamondRESUMEN
Fibroblast growth factor receptor 2 (FGFR2) is a crucial regulator of bone formation during embryonic development. Both gain and loss-of-function studies in mice have shown that FGFR2 maintains a critical balance between the proliferation and differentiation of osteoprogenitor cells. We have identified de novo FGFR2 mutations in a sporadically occurring perinatal lethal skeletal dysplasia characterized by poor mineralization of the calvarium, craniosynostosis, dysmorphic facial features, prenatal teeth, hypoplastic pubis and clavicles, osteopenia, and bent long bones. Histological analysis of the long bones revealed that the growth plate contained smaller hypertrophic chondrocytes and a thickened hypercellular periosteum. Four unrelated affected individuals were found to be heterozygous for missense mutations that introduce a polar amino acid into the hydrophobic transmembrane domain of FGFR2. Using diseased chondrocytes and a cell-based assay, we determined that these mutations selectively reduced plasma-membrane levels of FGFR2 and markedly diminished the receptor's responsiveness to extracellular FGF. All together, these clinical and molecular findings are separate from previously characterized FGFR2 disorders and represent a distinct skeletal dysplasia.
Asunto(s)
Enfermedades del Desarrollo Óseo/genética , Anomalías Craneofaciales/genética , Factores de Crecimiento de Fibroblastos/metabolismo , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismo , Secuencia de Aminoácidos , Enfermedades del Desarrollo Óseo/metabolismo , Huesos/anomalías , Huesos/embriología , Huesos/metabolismo , Condrocitos/metabolismo , Anomalías Craneofaciales/metabolismo , Feto/anomalías , Feto/metabolismo , Factores de Crecimiento de Fibroblastos/deficiencia , Heterocigoto , Humanos , Datos de Secuencia Molecular , Mutación , Mutación Missense , Osteoblastos/metabolismo , Osteogénesis/genética , Transducción de Señal , EsqueletoRESUMEN
The calvarial bones of the infant skull are connected by transient fibrous joints known as sutures and fontanelles, which are essential for reshaping during birth and postnatal growth. Genetic disorders such as Apert, Pfeiffer, Crouzon, and Bent bone dysplasia linked to FGFR2 variants often exhibit multi-suture craniosynostosis and a persistently open anterior fontanelle (AF). This study leverages mouse genetics and single-cell transcriptomics to determine how Fgfr2 regulates closure of the AF closure and its transformation into the frontal suture during postnatal development. We find that cells of the AF, marked by the tendon/ligament factor SCX, are spatially restricted to ecto- or endocranial domains and undergo regionally selective differentiation into ligament, bone, and cartilage. Differentiation of SCX+ AF cells is dependent on FGFR2 signaling in cells of the osteogenic fronts which, when fueled by FGF18 from the ectocranial mesenchyme, express the secreted WNT inhibitor WIF1 to regulate WNT signaling in neighboring AF cells. Upon loss of Fgfr2 , Wif1 expression is lost, and cells of the AF retain a connective tissue-like fate failing to form the posterior frontal suture. This study provides new insights into regional differences in suture development by identifying an FGF-WNT signaling circuit within the AF that links frontal bone advancement with suture joint formation.