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

Szenker‐Ravi, Emmanuelle; Ott, Tim; Khatoo, Muznah; Bellaing, Anne Moreau de; Goh, Wei Xuan; Chong, Yan Ling; Beckers, Anja; Kannesan, Darshini; Louvel, G.; Anujan, Priyanka; Ravi, Vydianathan; Bonnard, Carine; Moutton, Sébastien; Schoen, Patric; Fradin, Mélanie; Colin, Estelle; Mégarbané, André; Daou, Linda; Chehab, Ghassan; Filippo, Sylvie Di; Rooryck, Caroline; Deleuze, Jean‐François; Boland, Anne; Arribard, Nicolas; Eker, Rukiye; Tohari, Sumanty; Ng, Alvin; Rio, Marlène; Lim, Chun Teck; Eisenhaber, Birgit; Eisenhaber, Frank; Venkatesh, Byrappa; Amiel, Jeanne; Crollius, Hugues Roest; Gordon, Christopher T; Gossler, Achim; Roy, Sudipto; Attié‐Bitach, Tania; Blum, Martin; Bouvagnet, Patrice; Reversade, Bruno

doi:10.1038/s41588-021-00970-4

Cited by 21 publications

(15 citation statements)

References 91 publications

(100 reference statements)

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“…The direction of asymmetry might result from intracellular or cytoplasmic chirality that biases the production of one asymmetric morph over the other one by influencing the side of expression of certain morphogens (e.g. [66][67][68][69][70]). Under this scenario, subcellular asymmetries might favour the shift of thresholds consistently towards one direction, resulting in one morph having higher probability of fixation (e.g.…”

Section: Discussionmentioning

confidence: 99%

Genetic assimilation and the evolution of direction of genital asymmetry in anablepid fishes

et al. 2022

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Phylogenetic comparative studies suggest that the direction of deviation from bilateral symmetry (sidedness) might evolve through genetic assimilation; however, the changes in sidedness inheritance remain largely unknown. We investigated the evolution of genital asymmetry in fish of the family Anablepidae, in which males' intromittent organ (the gonopodium, a modified anal fin) bends asymmetrically to the left or the right. In most species, males show a 1 : 1 ratio of left-to-right-sided gonopodia. However, we found that in three species left-sided males are significantly more abundant than right-sided ones. We mapped sidedness onto a new molecular phylogeny, finding that this left-sided bias likely evolved independently three times. Our breeding experiment in a species with an excess of left-sided males showed that sires produced more left-sided offspring independently of their own sidedness. We propose that sidedness might be inherited as a threshold trait, with different thresholds across species. This resolves the apparent paradox that, while there is evidence for the evolution of sidedness, commonly there is a lack of support for its heritability and no response to artificial selection. Focusing on the heritability of the left : right ratio of offspring, rather than on individual sidedness, is key for understanding how the direction of asymmetry becomes genetically assimilated.

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Section: Discussionmentioning

confidence: 99%

Genetic assimilation and the evolution of direction of genital asymmetry in anablepid fishes

et al. 2022

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“…Similar post-transcriptional regulatory mechanisms generate LR asymmetry of Dand5 homologs in fish and frog (Hojo et al, 2007;Schweickert et al, 2010;Maerker et al, 2021). A recent phylogenetic study comparing vertebrates with motile cilia in their LRO versus those without cilia elucidated a set of 5 proteins lost in animals without a ciliated LRO (Szenker-Ravi et al, 2022).…”

Section: The Left-right Organizermentioning

confidence: 95%

“…Analyses of one of these proteins, a metalloprotease termed ciliated left right organizer metallopeptidase (CIROP), revealed that it functions as an upstream factor necessary for Dand5 asymmetry in mouse, frog and fish embryos, and that CIROP mutations are found in human laterality patients (Szenker-Ravi et al, 2022). How flow is sensed by LRO cells to asymmetrically impact CIROP, Bicc1, and potentially other regulators remains unclear.…”

Section: The Left-right Organizermentioning

confidence: 99%

Understanding laterality disorders and the left-right organizer: Insights from zebrafish

Forrest

Barricella²,

Pohar³

et al. 2022

Front. Cell Dev. Biol.

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Vital internal organs display a left-right (LR) asymmetric arrangement that is established during embryonic development. Disruption of this LR asymmetry—or laterality—can result in congenital organ malformations. Situs inversus totalis (SIT) is a complete concordant reversal of internal organs that results in a low occurrence of clinical consequences. Situs ambiguous, which gives rise to Heterotaxy syndrome (HTX), is characterized by discordant development and arrangement of organs that is associated with a wide range of birth defects. The leading cause of health problems in HTX patients is a congenital heart malformation. Mutations identified in patients with laterality disorders implicate motile cilia in establishing LR asymmetry. However, the cellular and molecular mechanisms underlying SIT and HTX are not fully understood. In several vertebrates, including mouse, frog and zebrafish, motile cilia located in a “left-right organizer” (LRO) trigger conserved signaling pathways that guide asymmetric organ development. Perturbation of LRO formation and/or function in animal models recapitulates organ malformations observed in SIT and HTX patients. This provides an opportunity to use these models to investigate the embryological origins of laterality disorders. The zebrafish embryo has emerged as an important model for investigating the earliest steps of LRO development. Here, we discuss clinical characteristics of human laterality disorders, and highlight experimental results from zebrafish that provide insights into LRO biology and advance our understanding of human laterality disorders.

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“…This evokes the concept of ‘functional modules’ where expression of a group of genes are tightly coordinated to act in the same developmental process ( Niehrs and Pollet, 1999 ; Szenker-Ravi et al, 2022 ), featuring essential gamete characteristics. For example, a module of meiosis contributes to halving the genome, whereas a module of folliculogenesis and spermatogenesis renders gametes feminized or masculinized, respectively.…”

Section: Model: Functionally Distinct Modules Integrate Gametogenesismentioning

confidence: 99%

Functional Modules in Gametogenesis

Kikuchi

Tanaka

2022

Front. Cell Dev. Biol.

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Gametogenesis, the production of eggs and sperm, is a fundamental process in sexually reproducing animals. Following gametogenesis commitment and sexual fate decision, germ cells undergo several developmental processes to halve their genomic size and acquire sex-specific characteristics of gametes, including cellular size, motility, and cell polarity. However, it remains unclear how different gametogenesis processes are initially integrated. With the advantages of the teleost fish medaka (Oryzias latipes), in which germline stem cells continuously produce eggs and sperm in mature gonads and a sexual switch gene in germ cells is identified, we found that distinct pathways initiate gametogenesis cooperatively after commitment to gametogenesis. This evokes the concept of functional modules, in which functionally interlocked genes are grouped to yield distinct gamete characteristics. The various combinations of modules may allow us to explain the evolution of diverse reproductive systems, such as parthenogenesis and hermaphroditism.

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

Cited by 21 publications

References 91 publications

Genetic assimilation and the evolution of direction of genital asymmetry in anablepid fishes

Genetic assimilation and the evolution of direction of genital asymmetry in anablepid fishes

Understanding laterality disorders and the left-right organizer: Insights from zebrafish

Functional Modules in Gametogenesis

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