Biology subjects

Moon, A. M.

Publications and source records attributed to Moon, A. M..

4 recordsLinked to original sources

bioRxiv2022

Tbx3 is required for mammalian retinal angiogenesis.

PurposeIn Retinopathy of Prematurity (ROP), infants often have incomplete vascularization, affecting the temporal region. A factor expressed in this region during retinal development is the T-box factor, Tbx3, which has not been studied in the mammalian eye. The purpose of this study was to determine if Tbx3 is required during eye formation for retinal angiogenesis. MethodsConditional removal of Tbx3 from both retinal progenitors and astrocytes was done using the optic cup-Cre recombinase driver, BAC-Dkk3-CRE and analyzed using standard immunohistochemical techniques. ResultsWith Tbx3 loss, the retinas were hypovascular, as seen in patients with ROP and Familial Exudative Vitreoretinopathy (FEVR). Retinal vasculature failed to form the stereotypic tri-layered plexus in the dorsal-temporal region. Astrocyte precursors were reduced in number and failed to form a lattice at the dorsal-temporal edge. We next examined retinal ganglion cells, as they have been shown to play a critical role in retinal angiogenesis. We found that melanopsin expression and Islet1/2-positive retinal ganglion cells were reduced in the dorsal half of the retina. In previous studies, loss of melanopsin has been linked to hyaloid artery persistence, which we also observed in the Tbx3 cKO retina, as well as in infants with ROP or FEVR. ConclusionsTogether, these results show that TBX3 is required for normal mammalian eye formation for the first time. This potentially provides a new genetic model for retinal hypovascular diseases.

neuroscience↗

bioRxiv2022

Fgf8 dosage regulates jaw shape and symmetry through pharyngeal-cardiac tissue relationships

BackgroundAsymmetries in craniofacial anomalies are commonly observed. With respect to the facial skeleton, the left side is more commonly and/or severely affected than the right. Such asymmetries complicate treatment options. Mechanisms underlying variation in disease severity between individuals as well as within individuals (asymmetries) are still relatively unknown. ResultsDevelopmental reductions in Fibroblast growth factor 8 (Fgf8) have a dosage dependent effect on jaw size, shape, and symmetry. Further, Fgf8 mutants have directionally asymmetric jaws with the left side being more affected than the right. Defects in lower jaw development begin with an early disruption to Meckels cartilage, which is discontinuous and appears as two separate condensations in Fgf8 mutants. All skeletal elements associated with the proximal condensation are dysmorphic in the mutants, which is exemplified by a malformed and mis-oriented malleus. At later stages, Fgf8 mutants exhibit syngnathia, which falls into 2 broad categories: bony fusion of the maxillary and mandibular alveolar ridges and zygomatico-mandibular fusion. All of these morphological defects exhibit both inter- and intra-individual variation. ConclusionsWe hypothesize that these asymmetries are linked to asymmetries in heart development resulting in higher levels of Fgf8 on the right side of the face during development, which may buffer the right side to mild developmental perturbations. This mutant mouse is a good model for future investigations of mechanisms underlying human syngnathia and facial asymmetry.

developmental biology↗

bioRxiv2021

FXR inhibition reduces ACE2 expression, SARS-CoV-2 infection and may improve COVID-19 outcome

Prevention of SARS-CoV-2 entry in cells through the modulation of viral host receptors, such as ACE2, could represent a new therapeutic approach complementing vaccination. However, the mechanisms controlling ACE2 expression remain elusive. Here, we identify the farnesoid X receptor (FXR) as a direct regulator of ACE2 transcription in multiple COVID19-affected tissues, including the gastrointestinal and respiratory systems. We demonstrate that FXR antagonists, including the over-the-counter compound z-guggulsterone (ZGG) and the off-patent drug ursodeoxycholic acid (UDCA), downregulate ACE2 levels, and reduce susceptibility to SARS-CoV-2 infection in lung, cholangiocyte and gut organoids. We then show that therapeutic levels of UDCA downregulate ACE2 in human organs perfused ex situ and reduce SARS-CoV-2 infection ex vivo. Finally, we perform a retrospective study using registry data and identify a correlation between UDCA treatment and positive clinical outcomes following SARS-CoV-2 infection, including hospitalisation, ICU admission and death. In conclusion, we identify a novel function of FXR in controlling ACE2 expression and provide evidence that this approach could be beneficial for reducing SARS-CoV-2 infection, thereby paving the road for future clinical trials.

microbiology↗

bioRxiv2019

A Hedgehog-FGF signaling axis patterns anterior mesoderm during gastrulation

The application of single cell technologies to early development holds promise for resolving complex developmental phenotypes. Here we define a novel role for Hedgehog (Hh) signaling for the formation of anterior mesoderm lineages during gastrulation. Single-cell transcriptome analysis of Hh-deficient mesoderm revealed selective deficits in anterior mesoderm populations that later translate to physical defects to anterior embryonic structures including the first pharyngeal arch, heart, and anterior somites. We found that Hh-dependent anterior mesoderm defects were cell non-autonomous to Hh-signal reception. Transcriptional profiling of Hh-deficient mesoderm during gastrulation revealed disruptions to both transcriptional patterning of the mesoderm and a key FGF signaling pathway for mesoderm migration. FGF4 protein application was able to restore cellular migration during gastrulation that was decreased by Hh pathway antagonism. These findings implicate that primitive streak-mediated regulation of anterior mesoderm patterning is controlled by a multicomponent signaling hierarchy activated by Hh signaling and executed by FGF signal transduction.\n\nSIGNIFICANCE STATEMENTHow signaling events during gastrulation pattern the mesoderm is a fascinating developmental process. Although Hedgehog signaling has been implicated in early mesoderm development, its mechanistic role has not been described. We applied single cell sequencing to describe mesodermal defects in Hedgehog pathway mutants--revealing selective defects in anterior mesoderm populations. Transcriptional profiling of gastrulating Hedgehog mutants indicated that several pathways essential for primitive streak function, including FGF, required Hh signaling. Blocking Hedgehog signaling abrogated cell migration during gastrulation, which could be mitigated by addition of FGF4 ligand. This work uncovers a novel Hedgehog to FGF signaling event and describes a unique mechanism by which signals from the node impact to anterior mesoderm formation through the modulation of primitive streak function.

developmental biology↗