Biology subjects

Kroeger, H.

Publications and source records attributed to Kroeger, H..

3 recordsLinked to original sources

bioRxiv2025

Atypical p38 Kinase Signaling in Retinal Vascular Damage and Recovery

Despite the life-changing impact of anti-VEGF therapies, vascular retinopathies continue to affect millions of patients worldwide. To better understand disease progression, it is essential to define alternative mechanisms that contribute to retinal vascular dysregulation. Mitogen-activated protein kinase (MAPK) p38 plays a significant role in regulating vascular homeostasis, angiogenesis, and retinal disease progression, yet effective therapeutic targeting remains elusive. An alternative atypical p38 signaling pathway is mediated by interaction with the adaptor protein TGF-beta activated kinase 1, binding protein 1 (TAB1). Atypical p38 can be activated by ischemia or by inflammatory G protein-coupled receptors (GPCRs) to regulate inflammation and vascular homeostasis. However, atypical signaling has not been investigated in the context of vascular retinopathies, specifically oxygen-induced retinopathy (OIR). Here, we utilized a genetic knock-in mouse to block atypical p38 activity (Tab1KI) to explore retinal damage during OIR. We report that Tab1KI mice display significantly reduced vaso-obliteration and limited neovascularization relative to wild-type C57BL6 controls. Retinal RNAseq analysis revealed distinct transcriptional regulation in the Tab1KI mouse. Suppression of atypical p38 reduced Mef2c signaling, which in turn enhanced microglial activation and inflammation. Despite the upregulation of proangiogenic markers, the increase in endothelial markers does not correlate with the dysregulated growth of blood vessels. Instead, Mef2c suppression reduces pathological angiogenesis, while increasing physiological vascular regrowth. The combined data suggest that the selective inhibition of atypical p38 signaling could block the enhanced pathogenic neovascular tuft formation without impacting blood vessel repair. Further investigation will clarify how atypical p38 controls neovascular responses, potentially revealing new treatment strategies for vascular retinopathies. NEW AND NOTEWORTHYMAPK p38 drives ocular injury and inflammation, but the contribution of Tab1-dependent atypical p38 in retinal injury has not been investigated. Using a mouse genetic knock-in model to block atypical p38 during oxygen-induced retinal injury, we show that atypical p38 enhances vascular damage and neovascular tufting. Blockade of atypical p38 protects mice from retinal vascular damage.

cell biology↗

bioRxiv2020

The Endoplasmic Reticulum Proteostasis Regulator ATF6 is Essential for Human Cone Photoreceptor Development

Dysregulation of the endoplasmic reticulum (ER) Unfolded Protein Response (UPR) is implicated in the pathology of many human diseases associated with ER stress. Inactivating genetic variants in the UPR regulator Activating Transcription Factor 6 (ATF6) cause severe congenital heritable vision loss in patients by an unknown pathomechanism. To investigate this, we generated retinal organoids from patient iPSCs carrying ATF6 disease-causing variants and ATF6 null hESCs generated by CRISPR. Interestingly, we found that cone photoreceptor cells in ATF6 mutant retinal organoids lacked inner and outer segments concomitant with absence of cone phototransduction gene expression; while rod photoreceptors developed normally. Adaptive optics retinal imaging of patients with disease-causing variants in ATF6 also showed absence of cone inner/outer segment structures but preserved rod structures, mirroring the phenotypes observed in our retinal organoids. These results reveal that ATF6 is essential for the formation of human cone photoreceptors, and associated absence of cone phototransduction components explains the severe visual impairment in patients with ATF6 -associated retinopathy. Moreover, we show that a selective small molecule ATF6 activator compound restores the transcriptional activity of ATF6 disease-causing variants and stimulates the growth of cone photoreceptors in patient retinal organoids, demonstrating that pharmacologic targeting of ATF6 signaling is a therapeutic strategy that needs to be further explored for blinding retinal diseases.

developmental biology↗

bioRxiv2018

Detailed analysis of chick optic fissure closure reveals Netrin-1 as an essential and conserved mediator of epithelial fusion during vertebrate embryogenesis.

Epithelial fusion underlies many vital organogenic processes during embryogenesis. Disruptions to these cause a significant number of human birth defects, including ocular coloboma. We provide robust spatial-temporal staging and unique anatomical detail of optic fissure closure (OFC) in the embryonic chick, including strong evidence for roles of apoptosis and epithelial remodelling. We performed complementary transcriptomic profiling and show that Netrin-1 (NTN1) is precisely expressed in the chick fissure margin at the fusion plate but is immediately downregulated after fusion. We further provide a combination of protein localisation and phenotypic evidence in chick, humans, mice and fish that Netrin-1 has an evolutionarily conserved and essential requirement for OFC, and is likely to have a major role in palate fusion. Our data reveal that NTN1 is a new locus for human coloboma and other multi-system developmental fusion defects, and that chick OFC is a powerful model for epithelial fusion research.

developmental biology↗