Type Ⅱ collagen (COLⅡ) is the primary constituent of the cartilage matrix, specifically present in vitreous bodies, cartilage, bone, and other skeletal elements. Therefore, the normal expression of COLⅡ is crucial for the normal development, linear growth, mechanical properties, and self-repairing ability of cartilage. Chondrocalcin, the C-propeptide of type Ⅱ procollagen, is not only a marker of COLⅡ synthesis but also one of the most abundant polypeptides in cartilage. This work examines the pivotal role of chondrocalcin in the synthesis of COLⅡ, comprehensively examining its regulation and multi-functions in cartilage and bone related diseases. Our findings suggest that mutations in the chondrocalcin-encoding domain of COL2A1 affect cartilage and bone development in clinical conditions.
{"title":"Chondrocalcin: Insights into its regulation and multi-function in cartilage and bone","authors":"Wensha Zhu , Zilong Zhao , Weigang Yuwen , Linlin Qu , Zhiguang Duan , Chenhui Zhu , Daidi Fan","doi":"10.1016/j.diff.2025.100861","DOIUrl":"10.1016/j.diff.2025.100861","url":null,"abstract":"<div><div>Type Ⅱ collagen (COLⅡ) is the primary constituent of the cartilage matrix, specifically present in vitreous bodies, cartilage, bone, and other skeletal elements. Therefore, the normal expression of COLⅡ is crucial for the normal development, linear growth, mechanical properties, and self-repairing ability of cartilage. Chondrocalcin, the C-propeptide of type Ⅱ procollagen, is not only a marker of COLⅡ synthesis but also one of the most abundant polypeptides in cartilage. This work examines the pivotal role of chondrocalcin in the synthesis of COLⅡ, comprehensively examining its regulation and multi-functions in cartilage and bone related diseases. Our findings suggest that mutations in the chondrocalcin-encoding domain of <em>COL2A1</em> affect cartilage and bone development in clinical conditions.</div></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"143 ","pages":"Article 100861"},"PeriodicalIF":2.2,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143725945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-01Epub Date: 2025-04-19DOI: 10.1016/j.diff.2025.100863
Dianshan Ke , Tingwei Gao , Hanhao Dai , Jie Xu, Tie Ke
ROS produced under oxidative stress are crucial for osteoclast differentiation. Metallothionein (MT) is a ROS-scavenging molecule. As a member of MT family, MT2 can clear ROS in osteoclast precursors (OCPs) and contributes to osteoclast differentiation. RANKL can promote OCP autophagy. Given the molecular-degrading effect of autophagy, the relationship between RANKL-dependent autophagy, MT2 and ROS during osteoclast differentiation is worth exploring. We depended in vitro RANKL administration and RANKL-overexpressing (Tg-RANKL) mice to observe the effects of RANKL on ROS production, MT2 protein expression, Beclin1 expression and autophagic activity in OCPs. Spautin1 was used to investigate the relationship between Beclin1-dependent autophagy and RANKL-regulated MT2 expression. Osteoclast-targeting MT2-cDNA-AAVs were applied to assess the therapeutic effect of MT2 on Tg-RANKL-related bone loss. The results showed that RANKL promoted ROS production but reduced MT2 protein expression in OCPs. RANKL also enhanced Beclin1 expression and LC3-puncta abundance. Decreased Beclin1 expression with spautin1 blocked RANKL-increased ROS production and osteoclast differentiation and recovered RANKL-decreased MT2 expression. MT2 selective overexpression with CD11b-promoter-MT2-cDNA-AAVs attenuated ROS production and osteoclastogenesis in Tg-RANKL mice and improved bone loss. Overall, RANKL can reduce MT2 protein expression through Beclin1-dependent autophagy, thereby promoting ROS production and osteoclast differentiation; this suggests that MT2-overexpressing small molecule drugs have the potential to treat RANKL-related bone loss.
{"title":"RANKL promotes MT2 degradation and ROS production in osteoclast precursors through Beclin1-dependent autophagy","authors":"Dianshan Ke , Tingwei Gao , Hanhao Dai , Jie Xu, Tie Ke","doi":"10.1016/j.diff.2025.100863","DOIUrl":"10.1016/j.diff.2025.100863","url":null,"abstract":"<div><div>ROS produced under oxidative stress are crucial for osteoclast differentiation. Metallothionein (MT) is a ROS-scavenging molecule. As a member of MT family, MT2 can clear ROS in osteoclast precursors (OCPs) and contributes to osteoclast differentiation. RANKL can promote OCP autophagy. Given the molecular-degrading effect of autophagy, the relationship between RANKL-dependent autophagy, MT2 and ROS during osteoclast differentiation is worth exploring. We depended <em>in vitro</em> RANKL administration and RANKL-overexpressing (Tg-RANKL) mice to observe the effects of RANKL on ROS production, MT2 protein expression, Beclin1 expression and autophagic activity in OCPs. Spautin1 was used to investigate the relationship between Beclin1-dependent autophagy and RANKL-regulated MT2 expression. Osteoclast-targeting MT2-cDNA-AAVs were applied to assess the therapeutic effect of MT2 on Tg-RANKL-related bone loss. The results showed that RANKL promoted ROS production but reduced MT2 protein expression in OCPs. RANKL also enhanced Beclin1 expression and LC3-puncta abundance. Decreased Beclin1 expression with spautin1 blocked RANKL-increased ROS production and osteoclast differentiation and recovered RANKL-decreased MT2 expression. MT2 selective overexpression with CD11b-promoter-MT2-cDNA-AAVs attenuated ROS production and osteoclastogenesis in Tg-RANKL mice and improved bone loss. Overall, RANKL can reduce MT2 protein expression through Beclin1-dependent autophagy, thereby promoting ROS production and osteoclast differentiation; this suggests that MT2-overexpressing small molecule drugs have the potential to treat RANKL-related bone loss.</div></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"143 ","pages":"Article 100863"},"PeriodicalIF":2.2,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01Epub Date: 2025-01-15DOI: 10.1016/j.diff.2025.100836
Cyril Andrieu , Cathy Danesin , Audrey Montigny , Marie Rey , Klara Baqué , Anne Bibonne , Dominique Alfandari , Eric Theveneau
Matrix Metalloproteinases (MMPs) are known for their role in matrix remodeling via their catalytic activities in the extracellular space. Interestingly, these enzymes can also play less expected roles in cell survival, polarity and motility via other substrates (e.g. receptors, chemokines), through an intracellular localization (e.g. the nucleus) or via non-catalytic functions. Most of these unconventional functions are yet to be functionally validated in a physiological context. Here, we used the delamination of the cephalic Neural Crest (NC) cells of the chicken embryo, a well described experimental model of epithelial-mesenchymal transition (EMT), to study the in vivo function of MMP14 (a.k.a MT1-MMP). MMP14 is a transmembrane MMP known for its importance in cell invasion and often associated with poor prognosis in cancer. We found that MMP14 is expressed and required for cephalic NC delamination. More specifically, MMP14 is necessary for the downregulation of Cadherin-6B and a co-inhibition of Cadherin-6B and MMP14 expressions is sufficient to restore NC delamination. Cadherin-6B is normally repressed by Snail2. Surprisingly, in MMP14 knockdown this lack of Cadherin-6B repression occurs in the context of a normal expression and nuclear import of Snail2. We further show that MMP14 is not detected in the nucleus and that Snail2 and MMP14 do not physically interact. These data reveals that a yet to be identified MMP14-dependent signaling event is required for the Snail2-dependent repression of Cadherin-6B. In conclusion, this work provides an in vivo example of atypical regulation of Cadherins by an MMP which emphasizes the importance and diversity of non-canonical functions of MMPs.
{"title":"Delamination of chick cephalic neural crest cells requires an MMP14-dependent downregulation of Cadherin-6B","authors":"Cyril Andrieu , Cathy Danesin , Audrey Montigny , Marie Rey , Klara Baqué , Anne Bibonne , Dominique Alfandari , Eric Theveneau","doi":"10.1016/j.diff.2025.100836","DOIUrl":"10.1016/j.diff.2025.100836","url":null,"abstract":"<div><div>Matrix Metalloproteinases (MMPs) are known for their role in matrix remodeling via their catalytic activities in the extracellular space. Interestingly, these enzymes can also play less expected roles in cell survival, polarity and motility via other substrates (e.g. receptors, chemokines), through an intracellular localization (e.g. the nucleus) or via non-catalytic functions. Most of these unconventional functions are yet to be functionally validated in a physiological context. Here, we used the delamination of the cephalic Neural Crest (NC) cells of the chicken embryo, a well described experimental model of epithelial-mesenchymal transition (EMT), to study the <em>in vivo</em> function of MMP14 (a.k.a MT1-MMP). MMP14 is a transmembrane MMP known for its importance in cell invasion and often associated with poor prognosis in cancer. We found that MMP14 is expressed and required for cephalic NC delamination. More specifically, MMP14 is necessary for the downregulation of Cadherin-6B and a co-inhibition of Cadherin-6B and MMP14 expressions is sufficient to restore NC delamination. Cadherin-6B is normally repressed by Snail2. Surprisingly, in MMP14 knockdown this lack of Cadherin-6B repression occurs in the context of a normal expression and nuclear import of Snail2. We further show that MMP14 is not detected in the nucleus and that Snail2 and MMP14 do not physically interact. These data reveals that a yet to be identified MMP14-dependent signaling event is required for the Snail2-dependent repression of Cadherin-6B. In conclusion, this work provides an <em>in vivo</em> example of atypical regulation of Cadherins by an MMP which emphasizes the importance and diversity of non-canonical functions of MMPs.</div></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"142 ","pages":"Article 100836"},"PeriodicalIF":2.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01Epub Date: 2025-01-30DOI: 10.1016/j.diff.2025.100838
Erica L. Benard , Matthias Hammerschmidt
Human wingless-type MMTV integration site family member 10A (WNT10A) is a secreted glycoprotein that is involved in signaling pathways essential to ectodermal organogenesis and tissue regeneration. WNT10A was first linked to human disorders in 2006, demonstrating a WNT10a variant to be associated with cleft lip with/without cleft palate. Numerous publications have since then identified the importance of WNT10A in the development of ectodermal appendages and beyond. In this review, we provide information on the structure of the WNT10A gene and protein, summarize its expression patterns in different animal models and in human, and describe the identified roles in tissue and organ development and repair in the different animal model organisms. We then correlate such identified functions and working mechanisms to the pathophysiology of a spectrum of human diseases and disorders that result from germline loss-of-function mutations in WNT10A, including ectodermal dysplasia (ED) syndromes Odonto-oncho-dermal dysplasia (OODD), Schöpf–Schulz–Passarge syndrome (SSPS), and selective tooth agenesis, as well as pathological conditions like fibrosis and carcinogenesis that can be correlated with increased WNT10A activity (Section 5).
{"title":"The fundamentals of WNT10A","authors":"Erica L. Benard , Matthias Hammerschmidt","doi":"10.1016/j.diff.2025.100838","DOIUrl":"10.1016/j.diff.2025.100838","url":null,"abstract":"<div><div>Human wingless-type MMTV integration site family member 10A (<em>WNT10A</em>) is a secreted glycoprotein that is involved in signaling pathways essential to ectodermal organogenesis and tissue regeneration. <em>WNT10A</em> was first linked to human disorders in 2006, demonstrating a <em>WNT10a</em> variant to be associated with cleft lip with/without cleft palate. Numerous publications have since then identified the importance of <em>WNT10A</em> in the development of ectodermal appendages and beyond. In this review, we provide information on the structure of the <em>WNT10A</em> gene and protein, summarize its expression patterns in different animal models and in human, and describe the identified roles in tissue and organ development and repair in the different animal model organisms. We then correlate such identified functions and working mechanisms to the pathophysiology of a spectrum of human diseases and disorders that result from germline loss-of-function mutations in <em>WNT10A</em>, including ectodermal dysplasia (ED) syndromes Odonto-oncho-dermal dysplasia (OODD), Schöpf–Schulz–Passarge syndrome (SSPS), and selective tooth agenesis, as well as pathological conditions like fibrosis and carcinogenesis that can be correlated with increased WNT10A activity (Section 5).</div></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"142 ","pages":"Article 100838"},"PeriodicalIF":2.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01Epub Date: 2024-10-30DOI: 10.1016/j.diff.2024.100818
Hiroyuki Yamaguchi , Matthew D. Meyer , William B. Barrell , Maryam Faisal , Rebecca Berdeaux , Karen J. Liu , Yoshihiro Komatsu
Primary cilia (hereafter “cilia”) are microtubule-based antenna-like organelles projecting from the surface of vertebrate cells. Cilia can serve as cellular antennae controlling cell growth and differentiation. Absent or dysfunctional cilia frequently lead to craniofacial anomalies known as craniofacial ciliopathies. However, the detailed pathological mechanisms of craniofacial ciliopathies remain unclear. This perspective discusses our current understanding of the role of cilia in cranial neural crest cells. We also describe potential mechanisms of ciliogenesis in cranial neural crest cells, which may contribute to unraveling the complex pathogenesis of craniofacial ciliopathies.
{"title":"The primary cilia: Orchestrating cranial neural crest cell development","authors":"Hiroyuki Yamaguchi , Matthew D. Meyer , William B. Barrell , Maryam Faisal , Rebecca Berdeaux , Karen J. Liu , Yoshihiro Komatsu","doi":"10.1016/j.diff.2024.100818","DOIUrl":"10.1016/j.diff.2024.100818","url":null,"abstract":"<div><div>Primary cilia (hereafter “cilia”) are microtubule-based antenna-like organelles projecting from the surface of vertebrate cells. Cilia can serve as cellular antennae controlling cell growth and differentiation. Absent or dysfunctional cilia frequently lead to craniofacial anomalies known as craniofacial ciliopathies. However, the detailed pathological mechanisms of craniofacial ciliopathies remain unclear. This perspective discusses our current understanding of the role of cilia in cranial neural crest cells. We also describe potential mechanisms of ciliogenesis in cranial neural crest cells, which may contribute to unraveling the complex pathogenesis of craniofacial ciliopathies.</div></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"142 ","pages":"Article 100818"},"PeriodicalIF":2.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01Epub Date: 2024-11-22DOI: 10.1016/j.diff.2024.100820
Amber D. Ide, Stephanie Grainger
WNT9 paralogues, WNT9A and WNT9B, are secreted ligands driving both the canonical (β-catenin dependent) and non-canonical (β-catenin independent) Wnt signaling pathways. These pathways play roles in cell fate determination, embryonic patterning, bone development, and organogenesis, among other biological processes. Studies of Wnt9a and Wnt9b mutant animals demonstrate that they have specific and overlapping roles in these processes. Wnt9a is critical in directing stem and progenitor cell fate during hematopoietic stem cell development, proper bone formation, and chondrogenesis, while Wnt9b is important for kidney and heart development. Both proteins are essential in craniofacial development and convergent extension movements. Dysregulated expression of human WNT9A and WNT9B have been implicated in different cancers and disease, suggesting these proteins or their downstream pathways may represent potential therapeutic targets.
{"title":"WNT9A and WNT9B in Development and Disease","authors":"Amber D. Ide, Stephanie Grainger","doi":"10.1016/j.diff.2024.100820","DOIUrl":"10.1016/j.diff.2024.100820","url":null,"abstract":"<div><div>WNT9 paralogues, WNT9A and WNT9B, are secreted ligands driving both the canonical (β-catenin dependent) and non-canonical (β-catenin independent) Wnt signaling pathways. These pathways play roles in cell fate determination, embryonic patterning, bone development, and organogenesis, among other biological processes. Studies of Wnt9a and Wnt9b mutant animals demonstrate that they have specific and overlapping roles in these processes. Wnt9a is critical in directing stem and progenitor cell fate during hematopoietic stem cell development, proper bone formation, and chondrogenesis, while Wnt9b is important for kidney and heart development. Both proteins are essential in craniofacial development and convergent extension movements. Dysregulated expression of human <em>WNT9A</em> and <em>WNT9B</em> have been implicated in different cancers and disease, suggesting these proteins or their downstream pathways may represent potential therapeutic targets.</div></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"142 ","pages":"Article 100820"},"PeriodicalIF":2.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Osteoblastogenesis is governed by complex interplays among signaling pathways, which modulate the expression of specific markers at each differentiation stage. This process enables osteoblast precursor cells to adopt the morphological and biochemical characteristics of mature bone cells. Our study investigates the role of NOTCH signaling in osteogenesis in MC3T3-E1 and C3H10T1/2 cell lines. MC3T3-E1 cells are preosteoblast precursors widely recognized as a model for bone biology research, offering a convenient and physiologically relevant system to study osteoblast transcriptional regulation. Conversely, the mesenchymal C3H10T1/2 cells are multipotent, capable of differentiating into osteoblasts, adipocytes, and chondrocytes under specific extracellular cues.
The core of this in vitro study is the comparative analysis of the impact of overexpressing each mammalian NOTCH receptor on osteoblastogenesis in two cell lines reflecting different cell differentiation stages. We generated stable transfectant pools of both cell lines for each of the four NOTCH receptors and characterized their effect on osteoblastogenesis. We successfully obtained transfectant pools that overexpress Notch1, Notch2 and Notch3 at both mRNA and protein levels. However, we were unable to obtain cells overexpressing Notch4 at protein level. Our findings reveal that the overexpression of NOTCH1, NOTCH2, and NOTCH3 receptors promotes osteoblast differentiation in mesenchymal C3H10T1/2 cells, while inhibiting it in preosteoblastic MC3T3-E1 cells. These results provide novel insights into the distinct roles of NOTCH receptors in osteoblastogenesis across two different precursor cell types, potentially guiding the development of new therapeutic approaches for bone diseases.
{"title":"NOTCH1, 2, and 3 receptors enhance osteoblastogenesis of mesenchymal C3H10T1/2 cells and inhibit this process in preosteoblastic MC3T3-E1 cells","authors":"Jose-Luis Resuela-González , María-Julia González-Gómez , María-Milagros Rodríguez-Cano , Susana López-López , Eva-María Monsalve , María-José M. Díaz-Guerra , Jorge Laborda , María-Luisa Nueda , Victoriano Baladrón","doi":"10.1016/j.diff.2025.100837","DOIUrl":"10.1016/j.diff.2025.100837","url":null,"abstract":"<div><div>Osteoblastogenesis is governed by complex interplays among signaling pathways, which modulate the expression of specific markers at each differentiation stage. This process enables osteoblast precursor cells to adopt the morphological and biochemical characteristics of mature bone cells. Our study investigates the role of NOTCH signaling in osteogenesis in MC3T3-E1 and C3H10T1/2 cell lines. MC3T3-E1 cells are preosteoblast precursors widely recognized as a model for bone biology research, offering a convenient and physiologically relevant system to study osteoblast transcriptional regulation. Conversely, the mesenchymal C3H10T1/2 cells are multipotent, capable of differentiating into osteoblasts, adipocytes, and chondrocytes under specific extracellular cues.</div><div>The core of this <em>in vitro</em> study is the comparative analysis of the impact of overexpressing each mammalian NOTCH receptor on osteoblastogenesis in two cell lines reflecting different cell differentiation stages. We generated stable transfectant pools of both cell lines for each of the four NOTCH receptors and characterized their effect on osteoblastogenesis. We successfully obtained transfectant pools that overexpress <em>Notch1</em>, <em>Notch2</em> and <em>Notch3</em> at both mRNA and protein levels. However, we were unable to obtain cells overexpressing <em>Notch4</em> at protein level. Our findings reveal that the overexpression of NOTCH1, NOTCH2, and NOTCH3 receptors promotes osteoblast differentiation in mesenchymal C3H10T1/2 cells, while inhibiting it in preosteoblastic MC3T3-E1 cells. These results provide novel insights into the distinct roles of NOTCH receptors in osteoblastogenesis across two different precursor cell types, potentially guiding the development of new therapeutic approaches for bone diseases.</div></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"142 ","pages":"Article 100837"},"PeriodicalIF":2.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143069356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01Epub Date: 2024-12-20DOI: 10.1016/j.diff.2024.100833
McLean H. Williamson, Wilson K. Clements
{"title":"WNT16 primer","authors":"McLean H. Williamson, Wilson K. Clements","doi":"10.1016/j.diff.2024.100833","DOIUrl":"10.1016/j.diff.2024.100833","url":null,"abstract":"","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"142 ","pages":"Article 100833"},"PeriodicalIF":2.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142900048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01Epub Date: 2024-12-10DOI: 10.1016/j.diff.2024.100831
Briana E. Pinales, Carlos E. Palomino, German Rosas-Acosta, Giulio Francia, Anita M. Quintana
Vitamin B12, otherwise known as cobalamin, is an essential water-soluble vitamin that is obtained from animal derived dietary sources. Mutations in the genes that encode proteins responsible for cobalamin uptake, transport, or processing cause inborn errors of cobalamin metabolism, a group of disorders characterized by accumulation of homocysteine and methylmalonic acid, neurodevelopmental defects, ocular dysfunction, anemia, and failure to thrive. Mild to moderate craniofacial phenotypes have been observed but these phenotypes are not completely penetrant and have not been consistently recognized in the literature. However, in the most recent decade, animal models of cblX and cblC, two cobalamin disorder complementation groups, have documented craniofacial phenotypes. These data indicate a function for cobalamin in facial development. In this review, we performed a literature review of all cobalamin complementation groups to identify which groups, and which human variants, are associated with dysmorphic features, microcephaly, or marfanoid phenotypes. We identified dysmorphic facial features in cblC, cblX, cblG, cblF, and cblJ, which are caused by mutations in MMACHC, HCFC1, MTR, LMBRD1, and ABCD4, respectively. Other complementation groups were associated primarily with microcephaly. Animal models (zebrafish and mouse) of cblC and cblX support these clinical phenotypes and have demonstrated neural crest cell deficits that include reduced expression of prdm1a, sox10, and sox9, key molecular markers of neural crest development. Characterization of a zebrafish mmachc germline mutant also suggests atypical chondrocyte development. Collectively, these data demonstrate an essential role for cobalamin in facial development and warrant future mechanistic inquiries that dissect the cellular and molecular mechanisms underlying human facial phenotypes in cobalamin disorders.
{"title":"Dissecting the role of vitamin B12 metabolism in craniofacial development through analysis of clinical phenotypes and model organism discoveries","authors":"Briana E. Pinales, Carlos E. Palomino, German Rosas-Acosta, Giulio Francia, Anita M. Quintana","doi":"10.1016/j.diff.2024.100831","DOIUrl":"10.1016/j.diff.2024.100831","url":null,"abstract":"<div><div>Vitamin B<sub>12</sub>, otherwise known as cobalamin, is an essential water-soluble vitamin that is obtained from animal derived dietary sources. Mutations in the genes that encode proteins responsible for cobalamin uptake, transport, or processing cause inborn errors of cobalamin metabolism, a group of disorders characterized by accumulation of homocysteine and methylmalonic acid, neurodevelopmental defects, ocular dysfunction, anemia, and failure to thrive. Mild to moderate craniofacial phenotypes have been observed but these phenotypes are not completely penetrant and have not been consistently recognized in the literature. However, in the most recent decade, animal models of <em>cblX</em> and <em>cblC</em>, two cobalamin disorder complementation groups, have documented craniofacial phenotypes. These data indicate a function for cobalamin in facial development. In this review, we performed a literature review of all cobalamin complementation groups to identify which groups, and which human variants, are associated with dysmorphic features, microcephaly, or marfanoid phenotypes. We identified dysmorphic facial features in <em>cblC</em>, <em>cblX</em>, <em>cblG</em>, <em>cblF</em>, and <em>cblJ</em>, which are caused by mutations in <em>MMACHC</em>, <em>HCFC1</em>, <em>MTR</em>, <em>LMBRD1</em>, and <em>ABCD4</em>, respectively. Other complementation groups were associated primarily with microcephaly. Animal models (zebrafish and mouse) of <em>cblC</em> and <em>cblX</em> support these clinical phenotypes and have demonstrated neural crest cell deficits that include reduced expression of <em>prdm1a</em>, <em>sox10</em>, and <em>sox9</em>, key molecular markers of neural crest development. Characterization of a zebrafish <em>mmachc</em> germline mutant also suggests atypical chondrocyte development. Collectively, these data demonstrate an essential role for cobalamin in facial development and warrant future mechanistic inquiries that dissect the cellular and molecular mechanisms underlying human facial phenotypes in cobalamin disorders.</div></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"142 ","pages":"Article 100831"},"PeriodicalIF":2.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01Epub Date: 2025-02-27DOI: 10.1016/j.diff.2025.100846
Joshua A. Moore , Loydie A. Jerome-Majewska
Splicing factors required for mRNA maturation have emerged as important contributors to neural crest development in the craniofacial region. Less is known of the role of these proteins in vagal neural crest cells that contribute to the outflow tract and form the enteric nervous system. In this review, we discuss the current state of our understanding of splicing and potential contribution of mis-splicing to cardiac and ENS defects.
{"title":"Are vagal neural crest derived tissues impacted in spliceosomopathies?","authors":"Joshua A. Moore , Loydie A. Jerome-Majewska","doi":"10.1016/j.diff.2025.100846","DOIUrl":"10.1016/j.diff.2025.100846","url":null,"abstract":"<div><div>Splicing factors required for mRNA maturation have emerged as important contributors to neural crest development in the craniofacial region. Less is known of the role of these proteins in vagal neural crest cells that contribute to the outflow tract and form the enteric nervous system. In this review, we discuss the current state of our understanding of splicing and potential contribution of mis-splicing to cardiac and ENS defects.</div></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"142 ","pages":"Article 100846"},"PeriodicalIF":2.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143587752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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