Inherited human (retinal) disease and cancer modeling
Our lab uses Xenopus tropicalis, an amphibian with a true diploid genome, to model human genetic diseases and cancer. We focus on (rare) Mendelian disorders, retinal degenerative disease and (pediatric) cancer. Our lab is at the frontline for the use of Xenopus tropicalis as a novel and powerful preclinical model.
Because of the size and the external embryonic development, CRISPR/Cas9 technologies are extremely efficient and very simple to apply in Xenopus. Due to its diploid genome, Xenopus tropicalis is emerging as an important organism for modeling human genetic disease, very complementary to the zebrafish.
Research Goals : Integrative whole genome and whole exome sequencing analysis is now routinely applied in diagnostic clinical settings. However, in many cases it remains a major challenge for the clinical geneticist to assign causality to specific mutations or aberrations encountered. Hence, versatile animal models are needed to quickly and efficiently test the function for these candidate disease genes. Likewise, advances in DNA sequencing over the past decade have made it possible to systematically analyze the genetic, genomic and epigenetic changes associated with different human cancers. This is exposing novel candidate driver mutations and opening roads for targeted molecular therapies for specific cancer subtypes. Preclinical genetic cancer models are required for rapidly discriminating driver and passenger mutations and identify novel targets for molecular therapy.
Areas of Expertise
- Modelling (rare) human genetic disorders in Xenopus tropicalis
- Generating genetic cancer models using CRISPR/Cas9 multiplexing
- Models for genetic retinal degenerative disease
- Development biology
- Cell biology
Technology Transfer Potential
- Molecular targets in human pathologies, including cancer
- Compound validation
- Van de Sompele, S. et al. Multi-omics approach dissects cis-regulatory mechanisms underlying North Carolina macular dystrophy, a retinal enhanceropathy. Am J Hum Genet 109, 2029-2048 (2022). Visit ➚
- Naert, T. et al. CRISPR-SID: Identifying EZH2 as a druggable target for desmoid tumors via in vivo dependency mapping. Proc Natl Acad Sci U S A 118, e2115116118 (2021). Visit ➚
- Naert, T. et al. Maximizing CRISPR/Cas9 phenotype penetrance applying predictive modeling of editing outcomes in Xenopus and zebrafish embryos. Sci Rep 10, 14662 (2020). Visit ➚
- Naert, T. et al. RBL1 (p107) functions as tumor suppressor in glioblastoma and small-cell pancreatic neuroendocrine carcinoma in Xenopus tropicalis. Oncogene 39, 2692-2706 (2020). Visit ➚
- Szenker-Ravi, E. et al. RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6. Nature 557, 564-569 (2018). Visit ➚
- Full bibliography Visit ➚
Mosaic mutant Xenopus tropicalis injected on its right site with TALENs targeting znrf3 and rnf43 (resulting in duplication of the fore limb) while its left side was injected with a CRISPR guide RNA targeting rspo2 (resulting in the absence of the fore limb) (see Szenker-Ravi et al., Nature 2018).