✍🏼 Alessandro Matera, Anne-Claire Compagnion, Chiara Pedicone, Janssen M. Kotah, Andranik Ivanov, Katia Monsorno, Gwenaël Labouèbe, Loredana Leggio, Marta Pereira-Iglesias, Dieter Beule, Virginie Mansuy-Aubert, Tim L. Williams, Nunzio Iraci, Amanda Sierra, Samuele G. Marro, Alison M. Goate, Bart J.L. Eggen, William G. Kerr, Rosa C. Paolicelli

🏠 Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland

📑 Immunity (2025)

Abstract
The gene inositol polyphosphate-5-phosphatase D (INPP5D), which encodes the lipid phosphatase SH2-containing inositol polyphosphate 5-phosphatase 1 (SHIP1), is associated with the risk of Alzheimer’s disease (AD). How it influences microglial function and brain physiology is unclear. Here, we showed that SHIP1 was enriched in early stages of healthy brain development. By combining in vivo loss-of-function approaches and proteomics, we discovered that mice conditionally lacking microglial SHIP1 displayed increased complement and synapse loss in the early postnatal brain. SHIP1-deficient microglia showed altered transcriptional signatures and abnormal synaptic pruning that was dependent on the complement system. Mice exhibited cognitive defects in adulthood only when microglial SHIP1 was depleted early postnatally but not at later stages. Induced pluripotent stem cell (iPSC)-derived microglia lacking SHIP1 also showed increased engulfment of synaptic structures. These findings suggest that SHIP1 is essential for proper microglia-mediated synapse remodeling in the healthy developing brain. Disrupting this process has lasting behavioral effects and may be linked to vulnerability to neurodegeneration.

How the WOLF is used in this study
In this article, the WOLF  was used during the generation of human INPP5D knockout induced pluripotent stem cell (iPSC) lines. Following CRISPR/Cas9-mediated genome editing of WTC-11 iPSCs, single cells were gently sorted into 96-well plates using the WOLF cell sorter to enable clonal isolation. Sorting was performed in mTeSR Plus medium supplemented with Chroman 1 to support cell survival and clonal expansion. This step was critical for the identification and expansion of homozygous INPP5D knockout clones, which were subsequently validated by PCR and Sanger sequencing and used for downstream differentiation into iPSC-derived microglia and functional assays.