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Discovery of a genetic module essential for assigning left-right asymmetry in humans and ancestral vertebrates

E. Szenker-Ravi 1 T. Ott 2 M. Khatoo 1 A. M. De Bellaing 3 W. X. Goh 1 Y. L. Chong 4, 5 A. Beckers 6, 7, 8 D. Kannesan 1 G. Louvel 9, 10 P. Anujan 4, 11 V. Ravi 4 C. Bonnard 12 S. Moutton 13 P. Schoen 14 M. Fradin 15 E. Colin 16 A. Megarbane 17, 18 L. Daou 19 G. Chehab 20, 19 S. Di Filippo 21, 3 C. Rooryck 22 J. F. Deleuze 23 A. Boland 23 N. Arribard 24 R. Eker 25 S. Tohari 4 A. Y. Ng 5 M. Rio 26, 27, 28 C. T. Lim 29, 30 B. Eisenhaber 30, 1 F. Eisenhaber 30, 1, 31 B. Venkatesh 4, 32 J. Amiel 33, 28 H. R. Crollius 9 C. T. Gordon 28 A. Gossler 7, 8 S. Roy 4, 32 T. Attie-Bitach 27 M. Blum 2, * P. Bouvagnet 34, * B. Reversade 1, 4, 32, 35, * 
* Corresponding author
Abstract : The vertebrate left-right axis is specified during embryogenesis by a transient organ: the left-right organizer (LRO). Species including fish, amphibians, rodents and humans deploy motile cilia in the LRO to break bilateral symmetry, while reptiles, birds, even-toed mammals and cetaceans are believed to have LROs without motile cilia. We searched for genes whose loss during vertebrate evolution follows this pattern and identified five genes encoding extracellular proteins, including a putative protease with hitherto unknown functions that we named ciliated left-right organizer metallopeptide (CIROP). Here, we show that CIROP is specifically expressed in ciliated LROs. In zebrafish and Xenopus, CIROP is required solely on the left side, downstream of the leftward flow, but upstream of DAND5, the first asymmetrically expressed gene. We further ascertained 21 human patients with loss-of-function CIROP mutations presenting with recessive situs anomalies. Our findings posit the existence of an ancestral genetic module that has twice disappeared during vertebrate evolution but remains essential for distinguishing left from right in humans.
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Submitted on : Wednesday, August 17, 2022 - 2:53:48 PM
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E. Szenker-Ravi, T. Ott, M. Khatoo, A. M. De Bellaing, W. X. Goh, et al.. Discovery of a genetic module essential for assigning left-right asymmetry in humans and ancestral vertebrates. Nature Genetics, Nature Publishing Group, 2022, 54 (1), pp.62-72. ⟨10.1038/s41588-021-00970-4⟩. ⟨inserm-03752860⟩

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