Biology subjects

Nagendren, L.

Publications and source records attributed to Nagendren, L..

3 recordsLinked to original sources

bioRxiv2026

Phosphatidylserine exposure by developing astrocytes initiates microglia-mediated developmental cell death

Developmental cell death is classically attributed to apoptosis, yet in mammalian retina, large numbers of developing astrocytes die non-apoptotically during a defined developmental window. Astrocyte death is important for patterning a cellular template that guides angiogenesis, but the underlying mechanism remains unknown. Here we show that healthy developing astrocytes initiate their own elimination by recruiting microglia via regulated exposure of the membrane lipid phosphatidylserine. Experimentally increasing phosphatidylserine exposure in astrocytes, but not neurons, accelerates their removal by microglia without changing how many astrocytes ultimately survive. This acceleration causes profound vascular defects resembling pathological features of retinopathy of prematurity. Genetic disruption of MFGE8, a phosphatidylserine-binding protein, suppresses microglia-mediated astrocyte killing and prevents vascular pathology despite continued phosphatidylserine exposure. This mechanism extends beyond the retina, because phosphatidylserine also initiates astrocyte death in developing cerebral cortex. Together, these findings identify phosphatidylserine exposure as a developmental signal that times microglia-mediated astrocyte elimination, with essential consequences for neurovascular development.

neuroscience↗

bioRxiv2025

Neuroligin-2 is ubiquitinated by Nedd4l to control developmental astrocyte morphogenesis.

Central nervous system astrocytes have an intricate, highly branched morphology. Proper development of perisynaptic astrocyte processes is necessary for tripartite synapse formation and function. However, cellular pathways orchestrating this development are largely unknown. Neuroligins (NLs) 1-3 regulate astrocyte morphogenesis via transcellular adhesions with neuronal neurexins. Here, we found an astrocytic NL2-based mechanism governing morphogenesis. Through structure and function studies, we identified a WW-binding motif within the NL2 intracellular domain required for astrocyte morphogenesis. Using cell-specific in vivo proximity labeling (iBioID), we found that each NL displays distinct protein-protein interactions within astrocytes, distinct from the neuronal NL2 binding partners. From these data, we identified a role for WW domain-containing E3 ubiquitin ligase Nedd4l in astrocyte morphogenesis. Biochemical assays revealed Nedd4l ubiquitinates and stabilizes NL2, and this ubiquitination is required for astrocyte morphogenesis. This study shows that Neuroligins have non-overlapping roles in controlling astrocyte growth and uncovers a molecular mechanism of how NL2 mediates astrocyte morphogenesis. SUMMARYSakers et al report that astrocytic neuroligins (NLs) are functionally diverse proteins, with unique intracellular protein-protein interactions. They show that Nedd4l binds to NL2 and ubiquitinates its intracellular domain, leading to changes in NL2 stability. In vivo, Nedd4l and NL2 ubiquitination are critical for astrocyte morphogenesis.

cell biology↗

bioRxiv2023

Astrocyte-Secreted Neurocan Controls Inhibitory Synapse Formation and Function

Astrocytes strongly promote the formation and maturation of synapses by secreted proteins. To date, several astrocyte-secreted synaptogenic proteins controlling different stages of excitatory synapse development have been identified. However, the identities of astrocytic signals that induce inhibitory synapse formation remain elusive. Here, through a combination of in vitro and in vivo experiments, we identified Neurocan as an astrocyte-secreted inhibitory synaptogenic protein. Neurocan is a chondroitin sulfate proteoglycan that is best known as a protein localized to the perineuronal nets. However, Neurocan is cleaved into two after secretion from astrocytes. We found that the resulting N- and C-terminal fragments have distinct localizations in the extracellular matrix. While the N-terminal fragment remains associated with perineuronal nets, the Neurocan C-terminal fragment localizes to synapses and specifically controls cortical inhibitory synapse formation and function. Neurocan knockout mice lacking the whole protein or only its C-terminal synaptogenic region have reduced inhibitory synapse numbers and function. Through super-resolution microscopy and in vivo proximity labeling by secreted TurboID, we discovered that the synaptogenic domain of Neurocan localizes to somatostatin-positive inhibitory synapses and strongly regulates their formation. Together, our results unveil a mechanism through which astrocytes control circuit-specific inhibitory synapse development in the mammalian brain.

neuroscience↗