Authors’ response to “Comment on: ‘Homozygous knockout of the piezo1 gene in the zebrafish is not associated with anemia’”

We welcome the Comment of Faucherre et al.1 in response to our correspondence2 concerning their report of hemolytic anemia in zebrafish embryos subjected to morpholino knockdown of piezo1.3 We note, however, that in their Comment, Faucherre et al. neither dispute nor question our descriptions or analyses2 of their paper on piezo1 morpholino knockdown.3 Nor do they question any of our data showing the absence of detectable anemia in zebrafish red cells from piezo1 germline knockout embryos and adults,2 a phenotype quite different from that reported in their morpholino knockdown studies.3 The rationale of Faucherre et al. for contributing their Comment seems rather to be based on the following contentions.

Faucherre et al. further note in their Comment that the “zebrafish piezo1 KO line …. appears to all intents and purposes to have no observable phenotype”[in contrast to the embryonic lethal vascular phenotype in KO mice]. We agree, and note in addition that recently described patients with autosomal recessive lymphatic dysplasia secondary to homozygous loss-of-function mutations in human PIEZO1 are remarkable for normal vasculature and an asymptomatic, fully compensated, very mild hemolytic state of incomplete penetrance.87

The concern of Faucherre et al. about these contrasting phenotypes associated with PIEZO1 loss-of-function only serves to highlight their curious choice not to report the vascular phenotype of their piezo1 morpholino knockdown fish, despite their commendable use of the Lmo2:dsRed reporter line3 (delineating vasculature as well as erythrocytes). Figure 3 from the original report by Faucherre et al. presents images of dsRed-expressing erythrocytes from morpholino-injected Lmo2:dsRed reporter line fish3 (which of the two morpholinos used was not described but seems to be MO1, assuming conditions of their Online Supplementary Figure S5 applied also to Figures 3 and 4). The absence of comment about a vascular phenotype in the dsRed-expressing blood vessels of this reporter line suggests the likelihood of normal vasculature, as was indeed observed in germline piezo1 fish by Kok et al.5 If so, the difference in vascular phenotype between the global knockout mouse and the PIEZO1-deficient fish would seem to be independent of whether the knockout mouse is compared to a morpholino knockdown fish or to a germline knockout fish.