Biology subjects

Bridges, C.

Publications and source records attributed to Bridges, C..

4 recordsLinked to original sources

bioRxiv2024

The level of endothelial glycocalyx maturity modulates interactions with charged nano-materials

Nanomaterials have been extensively investigated for their potential in delivering therapeutics to target tissues, but few have advanced to clinical application. The luminal surface of endothelial cells that line blood vessels are covered by a glycocalyx, a complex extracellular matrix rich in anionic glycans. However, the role of this glycocalyx in governing nanomaterial-cell interactions is often overlooked. In this study, we demonstrate that gold nanoparticles functionalized with branched polyethyleneimine (AuNP+) bind to primary human endothelial cells expressing either a developing or mature glycocalyx, with the interaction involving hyaluronan and heparan sulfate. Notably, the mature glycocalyx decreases the toxicity of AuNP+. In contrast, lipoic acid-functionalized gold nanoparticles (AuNP-) bind to endothelial cells with a developing glycocalyx, but not a mature glycocalyx. To further investigate this phenomenon, we studied charged polymers, including poly(arginine) (polyR) and poly(glutamic acid) (polyE). PolyE does not associate with endothelial cells regardless of glycocalyx maturity, but when glycans are enzymatically degraded, it can bind to the cells. Conversely, polyR associates with endothelial cells irrespective of glycocalyx maturity or glycan degradation. These findings highlight the intricate relationship between nanomaterial charge and presentation in interactions with endothelial cells, offering insights for modulating nanomaterial interactions with the blood vessel wall.

bioengineering↗

bioRxiv2021

EMX2 transcriptionally regulates Nfib expression in neural progenitor cells during early cortical development.

The nuclear factor one (NFI) transcription factors play key roles in regulating the onset of both neuronal and glial differentiation during cortical development. Reduced NFI expression results in delayed differentiation, which is associated with neurodevelopmental disorders in humans that include intellectual disability, agenesis of the corpus callosum and macrocephaly. Despite their importance, our understanding of how individual NFI family members are regulated during cortical development remains limited. Here, we demonstrate that in mice, the homeobox transcription factor EMX2 regulates Nfib expression in radial glial cells during cortical development. Using a combination of bioinformatics, molecular and histological approaches, we demonstrate that EMX2 is able to bind to the Nfib promoter to up-regulate Nfib expression. Unexpectedly, in vivo over-expression of EMX2 in wildtype animals does not further up-regulate NFIB but instead leads to its down-regulation. Therefore, our findings suggest that EMX2 is capable of both activating and repressing Nfib, in a context-dependent manner. This bi-directional control over Nfib expression enables fine-tuning of the total level of NFI proteins expressed and could be important for cell-type specific NFI functions.

neuroscience↗

bioRxiv2020

The DCC receptor regulates astroglial development essential for telencephalic morphogenesis and corpus callosum formation

The forebrain hemispheres are predominantly separated during embryogenesis by the interhemispheric fissure (IHF). Radial astroglia remodel the IHF to form a continuous substrate between the hemispheres for midline crossing of the corpus callosum (CC) and hippocampal commissure (HC). DCC and NTN1 are molecules that have an evolutionarily conserved function in commissural axon guidance. The CC and HC are absent in Dcc and Ntn1 knockout mice, while other commissures are only partially affected, suggesting an additional aetiology in forebrain commissure formation. Here, we find that these molecules play a critical role in regulating astroglial development and IHF remodelling during CC and HC formation. Human subjects with DCC mutations display disrupted IHF remodelling associated with CC and HC malformations. Thus, axon guidance molecules such as DCC and NTN1 first regulate the formation of a midline substrate for dorsal commissures prior to their role in regulating axonal growth and guidance across it.

neuroscience↗

bioRxiv2020

An essential role for MEF2C in the cortical response to loss of sleep

Neuronal activity and gene expression in response to the loss of sleep can provide a window into the enigma of sleep function. Sleep loss is associated with brain differential gene expression, an increase in pyramidal cell mEPSC frequency and amplitude, and a characteristic rebound and resolution of slow wave sleep-slow wave activity (SWS-SWA). However, the molecular mechanism(s) mediating the sleep loss response are not well understood. We show that sleep-loss regulates MEF2C phosphorylation, a key mechanism regulating MEF2C transcriptional activity, and that MEF2C function in postnatal excitatory forebrain neurons is required for the biological events in response to sleep loss. These include altered gene expression, the increase and recovery of synaptic strength, and the rebound and resolution of SWS-SWA, which implicate MEF2C as an essential regulator of sleep function. One Sentence SummaryMEF2C is critical to the response to sleep loss.

neuroscience↗