Pub Date : 2025-03-01DOI: 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}
Pub Date : 2025-03-01DOI: 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 : 2025-03-01DOI: 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 : 2025-03-01DOI: 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 : 2025-03-01DOI: 10.1016/j.diff.2025.100847
Alissa T. Rzepski , Mandy M. Schofield , Stephanie Richardson-Solorzano , Mark L. Arranguez , Alvin W. Su , Justin Parreno
Articular cartilage is an avascular tissue that allows for frictionless mobility of joints. Unfortunately, cartilage is incapable of self-repair and any damage leads to degradation in osteoarthritis (OA). Autologous chondrocyte implantation therapies are currently being used to treat focal cartilage defects caused by post-traumatic OA (PTOA). For chondrocyte implantation, chondrocytes are isolated from healthy regions of cartilage from damaged joints, expanded on stiff polystyrene to increase cell number, and reimplanted into damaged areas to stimulate repair. Unfortunately, chondrocyte implantations can ultimately fail as chondrocytes dedifferentiate during expansion. In dedifferentiation, chondrocytes increase in size, elongate, and express contractile cytoskeletal molecules. Furthermore, cells produce a fibroblastic matrix which is biomechanically inferior to articular cartilage matrix. Therefore, developing a greater understanding of dedifferentiation is imperative. In the dedifferentiation process, cellular actin filaments reorganize from a cortical organization into stress fibers. The formation of stress fibers plays a crucial role in chondrocyte dedifferentiation by regulating chondrocyte cell morphology and gene expression. Determining the actin-based molecular underpinnings in chondrocyte dedifferentiation may enable the specific targeting of stress fibers to promote redifferentiation of passaged cells and improve chondrocyte implantation outcomes. This review focuses on how targeting regulators of actin filament organization may promote the redifferentiation of expanded chondrocytes for implantation, thus increasing potential therapeuticlongevity.
{"title":"Targeting the reorganization of F-actin for cell-based implantation cartilage repair therapies","authors":"Alissa T. Rzepski , Mandy M. Schofield , Stephanie Richardson-Solorzano , Mark L. Arranguez , Alvin W. Su , Justin Parreno","doi":"10.1016/j.diff.2025.100847","DOIUrl":"10.1016/j.diff.2025.100847","url":null,"abstract":"<div><div>Articular cartilage is an avascular tissue that allows for frictionless mobility of joints. Unfortunately, cartilage is incapable of self-repair and any damage leads to degradation in osteoarthritis (OA). Autologous chondrocyte implantation therapies are currently being used to treat focal cartilage defects caused by post-traumatic OA (PTOA). For chondrocyte implantation, chondrocytes are isolated from healthy regions of cartilage from damaged joints, expanded on stiff polystyrene to increase cell number, and reimplanted into damaged areas to stimulate repair. Unfortunately, chondrocyte implantations can ultimately fail as chondrocytes dedifferentiate during expansion. In dedifferentiation, chondrocytes increase in size, elongate, and express contractile cytoskeletal molecules. Furthermore, cells produce a fibroblastic matrix which is biomechanically inferior to articular cartilage matrix. Therefore, developing a greater understanding of dedifferentiation is imperative. In the dedifferentiation process, cellular actin filaments reorganize from a cortical organization into stress fibers. The formation of stress fibers plays a crucial role in chondrocyte dedifferentiation by regulating chondrocyte cell morphology and gene expression. Determining the actin-based molecular underpinnings in chondrocyte dedifferentiation may enable the specific targeting of stress fibers to promote redifferentiation of passaged cells and improve chondrocyte implantation outcomes. This review focuses on how targeting regulators of actin filament organization may promote the redifferentiation of expanded chondrocytes for implantation, thus increasing potential therapeuticlongevity.</div></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"143 ","pages":"Article 100847"},"PeriodicalIF":2.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143593912","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 : 2025-03-01DOI: 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 : 2025-03-01DOI: 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 : 2025-03-01DOI: 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}
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":"2025-01-21","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 : 2025-01-01DOI: 10.1016/j.diff.2024.100829
Saurav Mohanty, Arne C. Lekven
The activation of sp5 in response to Wnt/β-catenin signaling is observed in many species during axis patterning, neural crest induction, maintenance and differentiation of stem cells. Indeed, the conserved response of sp5 orthologs to Wnt-mediated activation is the basis for this gene commonly being used as a readout for Wnt signaling activity. However, several seemingly conflicting findings regarding the function of sp5 in the context of Wnt signaling cast this gene in an enigmatic light. In this review, we examine current knowledge of sp5 structure and function, its relationship to Wnt signaling in varied contexts, and present perspectives on how progress on this interesting gene can move forward.
{"title":"Divergent functions of the evolutionarily conserved, yet seemingly dispensable, Wnt target, sp5","authors":"Saurav Mohanty, Arne C. Lekven","doi":"10.1016/j.diff.2024.100829","DOIUrl":"10.1016/j.diff.2024.100829","url":null,"abstract":"<div><div>The activation of <em>sp5</em> in response to Wnt/β-catenin signaling is observed in many species during axis patterning, neural crest induction, maintenance and differentiation of stem cells. Indeed, the conserved response of <em>sp5</em> orthologs to Wnt-mediated activation is the basis for this gene commonly being used as a readout for Wnt signaling activity. However, several seemingly conflicting findings regarding the function of <em>sp5</em> in the context of Wnt signaling cast this gene in an enigmatic light. In this review, we examine current knowledge of <em>sp5</em> structure and function, its relationship to Wnt signaling in varied contexts, and present perspectives on how progress on this interesting gene can move forward.</div></div>","PeriodicalId":50579,"journal":{"name":"Differentiation","volume":"141 ","pages":"Article 100829"},"PeriodicalIF":2.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830766","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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