Tcf12 controls dynamic calvarial bone growth and motor learning in mice
Abstract Heterozygous loss-of-function mutations ofTCF12andTWIST1can each cause craniosynostosis and neurodevelopmental delay in humans. Twist1-Tcf12 interaction plays an important role in regulating suture development. Although the molecular and cellular mechanisms underlying craniosynostosis and neurocognitive dysfunctions inTwist1+/-mice have been studied, less information on the role ofTcf12in these defects is available. To investigate the functional mechanism of Tcf12 in regulating skull and brain development, we analyzed the skull shape ofWnt1-Cre;Mesp1-Cre;Tcf12fl/flmice and found that, despite mild coronal synostosis, their skull shape appears to be similar to that of controls. We also found evidence of impaired motor learning ability inTcf12mutant mice. Furthermore, loss of Tcf12 in neural crest lineage leads to upregulatedRunx2expression in the calvarial mesenchyme and posterior expansion of the frontal bone inWnt1-Cre;Tcf12fl/flmice. Mechanistically, we show thatLmx1bis a direct downstream target of Tcf12 for the regulation of osteogenic differentiation in the calvarial mesenchyme during embryonic development. Importantly, overexpression ofLmx1binhibits osteogenic differentiation in the calvarial mesenchyme ofWnt1-Cre;Tcf12fl/flmice, indicating Tcf12’s regulation ofLmx1bexpression is crucial for controlling osteogenesis during calvarial bone development. Our study suggests that Tcf12 expression in the brain is crucial for motor learning. Moreover, this study establishes a new molecular mechanism underlying regulation of calvarial bone formation.Author Summary Craniosynostosis is characterized by premature fusion of cranial sutures and associated with abnormal skull growth, delayed brain development, and often impaired brain functions. Loss-of-function mutation ofTCF12can cause coronal synostosis and neurodevelopmental delay in humans. In developing mouse sutures,Tcf12is essential for maintaining the boundary between sutural and osteogenic cells. However, roles ofTcf12in skull formation and brain development have not been fully investigated. In this study, we show that loss ofTcf12leads to brain abnormalities even in the absence of coronal synostosis and that frontal bone expansion results from upregulated osteogenic differentiation in the calvarial mesenchyme in mice. Furthermore, we identifyLmx1bas a downstream target of Tcf12 for the regulation of osteogenic differentiation in the calvarial mesenchyme during frontal bone development. Our findings highlight the role of Tcf12 in the development of calvarial bones and provide new insight into molecular mechanisms for regulation of calvarial bone formation..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 10. Jan. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yamada, Takahiko [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2024.01.09.574781 |
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| PPN (Katalog-ID): |
XBI042126304 |
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| 520 | |a Abstract Heterozygous loss-of-function mutations ofTCF12andTWIST1can each cause craniosynostosis and neurodevelopmental delay in humans. Twist1-Tcf12 interaction plays an important role in regulating suture development. Although the molecular and cellular mechanisms underlying craniosynostosis and neurocognitive dysfunctions inTwist1+/-mice have been studied, less information on the role ofTcf12in these defects is available. To investigate the functional mechanism of Tcf12 in regulating skull and brain development, we analyzed the skull shape ofWnt1-Cre;Mesp1-Cre;Tcf12fl/flmice and found that, despite mild coronal synostosis, their skull shape appears to be similar to that of controls. We also found evidence of impaired motor learning ability inTcf12mutant mice. Furthermore, loss of Tcf12 in neural crest lineage leads to upregulatedRunx2expression in the calvarial mesenchyme and posterior expansion of the frontal bone inWnt1-Cre;Tcf12fl/flmice. Mechanistically, we show thatLmx1bis a direct downstream target of Tcf12 for the regulation of osteogenic differentiation in the calvarial mesenchyme during embryonic development. Importantly, overexpression ofLmx1binhibits osteogenic differentiation in the calvarial mesenchyme ofWnt1-Cre;Tcf12fl/flmice, indicating Tcf12’s regulation ofLmx1bexpression is crucial for controlling osteogenesis during calvarial bone development. Our study suggests that Tcf12 expression in the brain is crucial for motor learning. Moreover, this study establishes a new molecular mechanism underlying regulation of calvarial bone formation.Author Summary Craniosynostosis is characterized by premature fusion of cranial sutures and associated with abnormal skull growth, delayed brain development, and often impaired brain functions. Loss-of-function mutation ofTCF12can cause coronal synostosis and neurodevelopmental delay in humans. In developing mouse sutures,Tcf12is essential for maintaining the boundary between sutural and osteogenic cells. However, roles ofTcf12in skull formation and brain development have not been fully investigated. In this study, we show that loss ofTcf12leads to brain abnormalities even in the absence of coronal synostosis and that frontal bone expansion results from upregulated osteogenic differentiation in the calvarial mesenchyme in mice. Furthermore, we identifyLmx1bas a downstream target of Tcf12 for the regulation of osteogenic differentiation in the calvarial mesenchyme during frontal bone development. Our findings highlight the role of Tcf12 in the development of calvarial bones and provide new insight into molecular mechanisms for regulation of calvarial bone formation. | ||
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