Conditional depletion of WDFY3 in murine models of disease

This technology is a mouse model engineered to conditionally delete the autophagy-linked FYVE protein WDFY3, creating an effective research tool for studying autophagy, mitophagy, efferocytosis, and diseases impacted by these pathways, including neurodevelopmental and neurodegenerative disorders.

Unmet Need: In vivo model to study WDFY3 depletion

The autophagy-linked FYVE protein WDFY3 is a large multidomain scaffolding protein required for autophagy and clearance of damaged mitochondria (mitophagy). Loss of WDFY3 can result in neurodevelopmental delays and intellectual disabilities and has been linked to autism spectrum disorder and Huntington’s disease. The gene has also been shown to be required for macrophage efferocytosis, suggesting a role in resolving inflammation and chronic inflammatory diseases. Currently, there are no commercially available WDFY3-depleted mouse models, making it challenging to conduct in vivo analyses of this gene for research or therapeutic purposes.

The Technology: WDFY3 conditional knockout mouse model

This technology describes a mouse model generated to conditionally knock out the murine WDFY3 gene. In this model, the 5th exon of WDFY3 is flanked by loxP sites, which lead to the production of a truncated 66-amino-acid peptide after Cre-mediated recombination, thereby silencing the effect of the full-length 3,508-amino-acid Wdfy3 protein.

This technology has been experimentally validated in both the context of neurodevelopmental disorders and macrophage-dependent inflammation.

Applications:

• Research tool for the study of autophagy, mitophagy, and efferocytosis pathways
• Research tool for the study of neurodevelopmental disorders involving WDFY3, including autism spectrum disorder and epilepsy
• Research tool to study the buildup of protein aggregates in neurodegenerative diseases, like Huntington’s disease.

Advantages:

• Conditional system allows for better temporal and tissue-specific targeting of WDFY3 deletion
• Can be crossed with various Cre-based systems for personalization to specific experimental needs
• Provides a more biologically applicable model for disease study

Lead Inventor:

Ai Yamamoto, Ph.D.

Related Publications:

• Dragich JM, Kuwajima T, Hirose-Ikeda M, Yoon MS, Eenjes E, Bosco JR, Fox LM, Lystad AH, Oo TF, Yarygina O, Mita T, Waguri S, Ichimura Y, Komatsu M, Simonsen A, Burke RE, Mason CA, Yamamoto A. “Autophagy-linked FYVE (Alfy/WDFY3) is required for establishing neuronal connectivity in the mammalian brain.” Elife. 2016 Sep 20; 5:e14810.

• Croce KR, Ng C, Pankiv S, Albarran E, Langfelder P, Ramos de Jesus A, Duncan GM, Wang N, Basile A, McHugh C, Litt NA, Li A, Friedman S, Cortes EP, Zody MC, Yang XW, Ding JB, Vonsattel JPG, Simonsen A, Houseman DE, Wexler NS, Yamamoto A. “A rare genetic variant confers resistance to neurodegeneration across multiple neurological disorders by augmenting selective autophagy.” Neuron. 2025 Nov 18; 113(22): pp. 3780-3797.e7

Tech Ventures Reference:

• IR CU26114

• Licensing Contact: Kristin Neuman