Biology subjects

Aslanyan, M. G.

Publications and source records attributed to Aslanyan, M. G..

3 recordsLinked to original sources

bioRxiv2026

Primary cilia coordinate c-KIT signaling induced proliferation in alpha cells

Circulating glucagon levels are elevated in patients with diabetes and obesity and contribute to hyperglycemia. The mechanisms underlying hyperglucagonemia remain poorly understood, but expansion of pancreatic -cell mass is thought to play an important role. Primary cilia are sensory organelles that act as signaling hubs, for pathways controlling cell differentiation, proliferation, and function, yet their contribution to -cell biology remains poorly defined. Here we investigated the role of primary cilia in the regulation of -cell proliferation. To this end we generated the first -cell primary cilia proteome identifying 167 cilia-enriched proteins. Among these, we identified and validated the proto-oncogene receptor tyrosine kinase, c-KIT, as a novel ciliary receptor in -cells. We further show that c-KIT signaling depends on intact primary cilia and that stimulation of isolated mouse islets with its endogenous ligand, stem cell factor (SCF), promotes -cell proliferation. In human pancreatic islets KITLG mRNA expression, but not KIT mRNA expression, correlated positively with donor BMI, suggesting that increased ligand availability drives c-KIT signaling in obesity. Together, our findings identify the primary cilium as a signaling platform c-KIT in cells and reveal a ciliary axis that may drive -cell expansion and hyperglucagonemia in obesity and diabetes.

physiology↗

bioRxiv2025

Loss of INPP5E affects photoreceptor outer segment membrane biogenesis in iPSC-derived human retinal organoids

Mutations in the ciliary protein INPP5E, encoded by inositol polyphosphate-5-phosphatase E, can cause retinal degeneration as part of the ciliopathy Joubert Syndrome or non-syndromic retinitis pigmentosa (RP). INPP5E regulates the membrane makeup of the primary cilium, however its function in the specialized sensory photoreceptor cells of the human retina remain unclear. Here we utilize control and CRISPR/Cas9-generated INPP5E knock-out (INPP5EKD) human induced pluripotent stem cells (iPSCs) to generate retinal organoids (ROs). Through proteomic and immunofluorescence analysis we show that INPP5E plays an important role in early retinal development and photoreceptor progenitor cell differentiation. In mature ROs, INPP5E localizes to the connecting cilium of photoreceptors, and the loss of INPP5E leads to altered localization of ARL13B and Rhodopsin in mature photoreceptors. Furthermore, photoreceptor outer segment structure is affected, leading to elongated outer segment membranes in both cone and rod photoreceptors, suggesting an important role for INPP5E in photoreceptor outer segment membrane biogenesis. Together, these data underline the importance of INPP5E in retina development and photoreceptor structure and highlight the usability of retinal organoids to study protein function in a human context.

cell biology↗

bioRxiv2018

Mutations In PIK3C2A Cause Syndromic Short Stature, Skeletal Abnormalities, and Cataracts Associated With Ciliary Dysfunction

PIK3C2A is a class II member of the phosphoinositide 3-kinase (PI3K) family that catalyzes the phosphorylation of phosphatidylinositol (PI) into PI(3)P and the phosphorylation of PI(4)P into PI(3,4)P2. We identified homozygous loss-of-function mutations in PIK3C2A in children from three independent consanguineous families with short stature, coarse facial features, cataracts with secondary glaucoma, multiple skeletal abnormalities, neurological manifestations, among other findings. Cellular studies of patient-derived fibroblasts found that they lacked PIK3C2A protein, had impaired cilia formation and function, and demonstrated reduced proliferative capacity. Collectively, the genetic and molecular data implicate mutations in PIK3C2A in a new Mendelian disorder of PI metabolism, thereby shedding light on the critical role of a class II PI3K in growth, vision, skeletal formation and neurological development. This discovery expands what is known about disorders of PI metabolism and helps unravel the role of PIK3C2A and class II PI3Ks in health and disease.

genetics↗