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bioRxiv2024

Iron chelation by oral deferoxamine treatment decreased brain iron and iron signaling proteins

BackgroundDeferoxamine (DFO) and other iron chelators are clinically used for cancer and stroke. They may also be useful for Alzheimers disease (AD) to diminish iron from microbleeds. DFO may also stimulate antioxidant membrane repair which is impaired during AD. DFO, and other chelators do enter the brain despite some contrary reports. ObjectiveLow dose, oral DFO was given in lab chow to wildtype (WT) C57BL/6 mice to evaluate potential impact on iron levels, iron-signaling and storage proteins, and amyloid precursor protein (APP) and processing enzymes. Young WT mice do not have microbleeds or disrupted blood-brain barrier of AD mice. MethodsIron was measured by MRI and chemically after two weeks of dietary DFO. Cerebral cortex was examined for changes in iron metabolism, antioxidant signaling, and APP processing by Western blot. ResultsDFO decreased brain iron by 18% (MRI) and decreased seven major proteins that mediate iron metabolism by at least 25%. The iron storage proteins ferritin light and heavy chain decreased by at least 30%. APP and secretase enzymes also decreased by 30%. ConclusionsWT mice respond to DFO with decreased APP, amyloid processing enzymes, and antioxidant repair. Potential DFO treatment for early-stage AD by DFO should consider the benefits of lowered APP and secretase enzymes.

neuroscience↗

bioRxiv2024

Tcf12 controls dynamic calvarial bone growth and motor learning in mice

Heterozygous loss-of-function mutations of TCF12 and TWIST1 can 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 in Twist1+/- mice have been studied, less information on the role of Tcf12 in these defects is available. To investigate the functional mechanism of Tcf12 in regulating skull and brain development, we analyzed the skull shape of Wnt1-Cre;Mesp1-Cre;Tcf12fl/fl mice 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 in Tcf12 mutant mice. Furthermore, loss of Tcf12 in neural crest lineage leads to upregulated Runx2 expression in the calvarial mesenchyme and posterior expansion of the frontal bone in Wnt1-Cre;Tcf12fl/fl mice. Mechanistically, we show that Lmx1b is a direct downstream target of Tcf12 for the regulation of osteogenic differentiation in the calvarial mesenchyme during embryonic development. Importantly, overexpression of Lmx1b inhibits osteogenic differentiation in the calvarial mesenchyme of Wnt1-Cre;Tcf12fl/fl mice, indicating Tcf12s regulation of Lmx1b expression 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 SummaryCraniosynostosis 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 of TCF12 can cause coronal synostosis and neurodevelopmental delay in humans. In developing mouse sutures, Tcf12 is essential for maintaining the boundary between sutural and osteogenic cells. However, roles of Tcf12 in skull formation and brain development have not been fully investigated. In this study, we show that loss of Tcf12 leads 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 identify Lmx1b as 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.

developmental biology↗