Biology subjects

Norton, V.

Publications and source records attributed to Norton, V..

2 recordsLinked to original sources

bioRxiv2026

Mechanistic Insights into MYO1C-Mediated Rhodopsin Trafficking and Rod Photoreceptor Homeostasis.

Rhodopsin trafficking from the photoreceptor inner segment to the outer segment is essential for photoreceptor function, yet the molecular mechanism(s) regulating this process remain incompletely understood. MYO1C is an actin-based motor protein implicated in intracellular cargo trafficking. Here, we investigated its role in rhodopsin trafficking and photoreceptor cell homeostasis. In-silico docking identified a putative interaction between the MYO1C C-terminal region and the C-terminal region of rhodopsin containing the conserved VxPx ciliary trafficking motif. Biochemical studies confirmed that full-length MYO1C interacts with rhodopsin, whereas deletion of the MYO1C C-terminal domain abolished this interaction. Live-cell imaging, ciliary localization, and fluorescence recovery after photobleaching in hTERT-RPE1 cells demonstrated that the MYO1C C-terminal region is required for efficient rhodopsin trafficking, membrane localization, and ciliary targeting. In native murine rod photoreceptors MYO1C localized to both inner and outer segments. Global Myo1c deficiency in mice caused age-dependent rhodopsin mislocalization, apo-opsin accumulation and progressive retinal dysfunction, characterized primarily by reduced scotopic ERG responses and delayed a-wave recovery, beginning at 6-months, while photopic responses were relatively preserved. Rod-specific Myo1c deletion similarly caused progressive scotopic dysfunction and reduced a-wave recovery following light stimulation. In contrast, cone-specific Myo1c deletion preserved photopic function and a-wave recovery. Together, these findings identify MYO1C as an important regulator of rhodopsin trafficking and demonstrate a preferential, cell-autonomous requirement for MYO1C in maintaining rod photoreceptor homeostasis and phototransduction recovery. These findings establish a mechanistic link between MYO1C-dependent rhodopsin trafficking and age-dependent rod photoreceptor cell dysfunction.

cell biology↗

bioRxiv2023

Targeting endothelial FOXO1 protects diabetic β-cells and improves wound healing

The forkhead box O1 (FOXO1) transcription factor plays critical roles in regulating not only metabolic activity but also angiogenesis in the vascular endothelium1-4. Our previous studies show that epsin endocytic adaptors can regulate both angiogenesis and lymphangiogenesis5-7. Endothelial cells (ECs) lining the inside of blood vessels are continuously exposed to circulating insulin and insulin-like growth factors (IGFs). Emerging evidences suggest that ECs can affect {beta}-cell function8-11. Excessive IGF2, especially elevated local IGF2 levels in islets, may represent a risk factor for developing diabetes12-15; however, the underlying molecular mechanisms by which aberrant angiogenesis and endothelium-derived factors regulate pancreatic {beta}-cell function in diabetes remain unclear. Here, we report that the pancreas of diabetic patients as well as the pancreas, skin, and plasma of streptozotocin/high fat diet (STZ/HFD)-induced diabetic mice and db/db mice contains excess IGF2, which can lead to {beta}-cell dysfunction and apoptosis. Single-cell transcriptomics combined with mass spectrometry analysis reveal that endothelial-specific knockout of FOXO1 increases circulating soluble and cell-membrane or intracellular expression levels of IGF type 2 receptor (IGF2R) and CCCTC-binding factor (CTCF), while decreasing IGF2 levels in diabetes. Both IGFR215-17 and CTCF18-21 can reduce IGF2 levels and may ameliorate {beta}-cell decline associated with excess IGF2 in diabetes. Furthermore, depletion of FOXO1, epsins, or knockdown of ULK1 inhibits autophagy formation in ECs, preventing degradation of vascular endothelial growth factor receptor 2 (VEGFR2) to promote angiogenesis and improve wound healing in diabetes. Our findings reveal that endothelial FOXO1 regulates epsin-dependent angiogenesis and affects {beta}-cell function and fate through CTCF and IGF2-IGF2R, providing a potential strategy for ameliorating diabetes and accelerating cutaneous wound healing.

cell biology↗