Drosophila Bchs overexpression recapitulates human WDFY3 neurodevelopmental phenotypes with implications for glial cell involvement in altered head circumference

Koerner, M. B.; Velluva, A.; Bundalian, L.; Krohn, K.; Schoen, K.; Schumann, I.; Kromp, J.; Thum, A. S.; Garten, A.; Hentschel, J.; Abou Jamra, R.; Mrestani, A.; Scholz, N.; Langenhan, T.; Le Duc, D.

doi:10.1101/2023.10.16.562295

bioRxiv · 10.1101/2023.10.16.562295

Drosophila Bchs overexpression recapitulates human WDFY3 neurodevelopmental phenotypes with implications for glial cell involvement in altered head circumference

Koerner, M. B.·Velluva, A.·Bundalian, L.·Krohn, K.·Schoen, K.·Schumann, I.·Kromp, J.·Thum, A. S.·Garten, A.·Hentschel, J.·Abou Jamra, R.·Mrestani, A.·Scholz, N.·Langenhan, T.·Le Duc, D.

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Abstract

The autophagy adaptor WDFY3 is linked to neurodevelopmental delay and altered brain size. Loss-of-function variants are associated with an increased brain size in both humans and mice. We thus, hypothesized that the microcephaly observed in some of the patients may be related to a gain-of-function of the WDFY3 gene product. While the role of WDFY3 loss-of-function has been studied extensively in neurons, little is known about the effects of WDFY3 overexpression in different neural cell types. We utilized a Drosophila melanogaster overexpression model to investigate the effect of the WDFY3 ortholog Bchs (blue cheese) on development, CNS size, and gene expression profiles. Glial and neuronal overexpression of Bchs impaired CNS development, locomotion and autophagy. Glial overexpression of Bchs also altered CNS size significantly. We identified 79 genes that were differentially expressed and overlapped in flies that overexpress Bchs in glial and neuronal cells, respectively. Additionally, upon neuronal Bchs overexpression differentially expressed genes clustered in gene ontology categories associated with autophagy and mitochondria. Our data indicate that WDFY3/Bchs overexpression in both neurons and glial cells results in impaired neural development, which corresponds to symptoms observed in WDFY3-related neurodevelopmental delay.

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Koerner, M. B., Velluva, A., Bundalian, L., Krohn, K., Schoen, K., Schumann, I., Kromp, J., Thum, A. S., Garten, A., Hentschel, J., Abou Jamra, R., Mrestani, A., Scholz, N., Langenhan, T., Le Duc, D.. 2023-10-17. Drosophila Bchs overexpression recapitulates human WDFY3 neurodevelopmental phenotypes with implications for glial cell involvement in altered head circumference. https://doi.org/10.1101/2023.10.16.562295

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