Burnett, L. C. | bioRxiv Science

bioRxiv2025

The Preclinical Animal Network (PCAN): Integrative high-throughput phenotyping of standardized mouse models for Prader-Willi syndrome

The Preclinical Animal Network (PCAN) is a collaborative resource established to advance translational research and therapeutic development for Prader-Willi syndrome (PWS), a rare neurodevelopmental disorder caused by loss of paternally expressed genes on chromosome 15q11-q13. PCAN integrates standardized, high-throughput phenotyping of approximately 1,000 mice across six engineered lines carrying paternal deletions of Ndn, Magel2, Snord116, Ipw, and multigenic loci. Using validated experimental pipelines spanning metabolic, behavioral, and developmental domains, we captured comprehensive phenotypic profiles by applying a statistical variance-decomposition framework to partition genetic and environmental contributions. This analysis provides robust genotype-phenotype maps, revealing shared and model-specific phenotypic effects while accounting for key confounding factors. The PCAN resource provides a framework for evaluating PWS-relevant phenotypes and benchmarking therapeutic strategies. By providing open access to its mouse models, datasets and analytical resources, PCAN enables the research community to apply standardized, reproducible workflows and accelerate the development of targeted, mechanism-based treatments.

genetics↗

bioRxiv2020

Regulation of intracellular signaling and neuron function by Bardet-Biedl Syndrome proteins in patient-specific iPSC-derived neurons

Bardet-Biedl Syndrome (BBS) is a rare autosomal recessive disorder caused by mutations in genes encoding components of the primary cilium and characterized by hyperphagic obesity. We developed a cellular model of BBS using induced pluripotent stem cell (iPSCs)-derived hypothalamic arcuate-like neurons. BBS mutations BBS1M390R and BBS10C91fsX95 did not affect neuron differentiation efficiency but caused morphological defects including impaired neurite outgrowth and longer primary cilia. Expression of intact BBS10 normalized cilia length. Single-cell RNA sequencing (scRNA-seq) of BBS1M390R hypothalamic neurons identified several down regulated pathways including insulin and cAMP signaling, and axon guidance. In agreement with scRNA-seq data, insulin-induced AKT phosphorylation at Thr308 was reduced in BBS1M390R and BBS10c91fsX95 human fibroblasts and iPSC-derived neurons, as well as in BBS10 knockdown iPSC-derived neurons. Overexpression of intact BBS10 fully restored insulin receptor tyrosine phosphorylation in BBS10c91fsX95 neurons. Mutations in BBS1 and BBS10 impaired leptin-mediated p-STAT3 activation in both human primary fibroblasts and iPSC-derived hypothalamic neurons. Correction of the BBS mutation by CRISPR rescued leptin signaling. POMC expression in BBS1M390R and BBS10 C91fsX95 iPSC-derived hypothalamic neurons was downregulated, as was hypothalamic Pomc in BBS1M390R knockin (KI) mice. In the aggregate, these data provide insights into the anatomic and functional mechanisms by which components of the BBsome in CNS primary cilia mediate effects on energy homeostasis.

cell biology↗