ABSTRACT
First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping researchers promote themselves alongside their papers. Xuming Zhu is first author on ‘ FZD2 regulates limb development by mediating β-catenin-dependent and -independent Wnt signaling pathways’, published in DMM. Xuming is an instructor in the lab of Sarah E. Millar at Icahn School of Medicine at Mount Sinai, New York, NY, USA, investigating the molecular mechanisms that underlie the development of appendages, epithelial homeostasis and diseases.
Xuming Zhu
How would you explain the main findings of your paper to non-scientific family and friends?
Human Robinow syndrome (RS) and dominant omodysplasia type 2 (OMOD2), characterized by skeletal limb and craniofacial defects, are associated with heterozygous mutations in the FZD2 gene. However, the precise functions of FZD2 in limb development are unclear. We generated mouse models that have defective FZD2 function, which causes shortened limbs, resembling those of RS and OMOD2 patients, indicating that FZD2 mutations are causative. We also investigated the molecular mechanism that underlies the role of FZD2 in controlling limb development using our mouse models.
“[…] FZD2 regulates limb development by mediating canonical and non-canonical Wnt signaling pathways […]”
What are the potential implications of these results for your field of research?
Our results demonstrate that FZD2 regulates limb development by mediating canonical and non-canonical Wnt signaling pathways, and further extend our knowledge about the role of Wnt receptors in controlling limb development.
What are the main advantages and drawbacks of the experimental system you have used as it relates to the disease you are investigating?
The main advantage of our experimental system is that we generated Fzd2 mouse models that show similar limb defects to human patients harbouring FZD2 mutations, and we performed in vivo experiments to study the function of FZD2 in limb development. However, our mouse models do not have mutations that are identical to those of human patients.
Fzd2 expression in the limb bud mesenchyme at E10.5 is repressed by stabilized β-catenin, as indicated by RNAscope and quantitative PCR. (A,B) Expression of Fzd2 in control (A) and mutant (B) forelimb bud at E10.5. Expression of Fzd2 in the mutant forelimb bud mesenchyme is significantly reduced by excessive canonical Wnt signaling, which is caused by stabilized β-catenin. (C) Fzd2 mRNA expression is reduced in the forelimb bud mesenchyme upon β-catenin stabilization, whereas the mRNA expression of Wnt target genes Lef1 and Axin2 is significantly upregulated. Thus, expression of Fzd2 is negatively regulated by the Wnt/β-catenin signaling pathway. E, embryonic day; FL, forelimb. Scale bars: 100 μm.
Fzd2 expression in the limb bud mesenchyme at E10.5 is repressed by stabilized β-catenin, as indicated by RNAscope and quantitative PCR. (A,B) Expression of Fzd2 in control (A) and mutant (B) forelimb bud at E10.5. Expression of Fzd2 in the mutant forelimb bud mesenchyme is significantly reduced by excessive canonical Wnt signaling, which is caused by stabilized β-catenin. (C) Fzd2 mRNA expression is reduced in the forelimb bud mesenchyme upon β-catenin stabilization, whereas the mRNA expression of Wnt target genes Lef1 and Axin2 is significantly upregulated. Thus, expression of Fzd2 is negatively regulated by the Wnt/β-catenin signaling pathway. E, embryonic day; FL, forelimb. Scale bars: 100 μm.
What has surprised you the most while conducting your research?
It is unusual that one FZD receptor can mediate multiple Wnt pathways in the same context. Therefore, I am surprised that FZD2 can mediate both canonical and noncanonical Wnt signaling pathways in limb bud mesenchyme.
What do you think is the most significant challenge impacting your research at this time and how will this be addressed over the next 10 years?
The most significant challenge will be finding a way to precisely diagnose and correct the FZD2 mutations in vivo. Thanks to the decreasing cost of whole-genome sequencing and the development of more-efficient and safer gene-editing technology such as CRISPR, it will be possible in the future to treat patients harbouring pathological FZD2 mutations.
What changes do you think could improve the professional lives of scientists?
I think the evolving artificial intelligence and machine-learning technology will help scientists to design more reasonable experiments. It will also be very helpful to find a way to better utilize the large collection of profiling data in public databases.
What's next for you?
I will continue to pay attention to the research of Wnt signaling pathways in limb development, especially how Fzd2 expression is regulated. I am also interested in investigating the function of epigenetic regulators in controlling limb development.
Xuming Zhu's contact details: Black Family Stem Cell Institute and Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
E-mail: [email protected]