Left–Right Patterning: Breaking Symmetry to Asymmetric Morphogenesis

Grimes, Daniel T.; Burdine, Rebecca D.

doi:10.1016/j.tig.2017.06.004

Cited by 123 publications

(115 citation statements)

References 88 publications

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“…Because organ laterality is regulated by evolutionally conserved asymmetric L-R gene expression in vertebrates, we next examined the expression patterns of spaw and its downstream gene pitx2c [1,38]. At the late somite stages, we observed spaw and pitx2c expression in the left LPM in wild-type embryos, whereas expression of these genes was found to be bilateral or absent in cxcr4a um20 mutants and DFC 4a MO embryos (Fig 1I-1N).…”

Section: Resultsmentioning

confidence: 99%

Chemokine signaling links cell cycle progression and cilia formation for left-right symmetry breaking

Zhu

Guan

et al. 2019

Preprint

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23 Zebrafish dorsal forerunner cells (DFCs) undergo vigorous proliferation during 24 epiboly and then exit cell cycle to generate Kupffer's vesicle (KV), a ciliated organ 25 necessary for establishing left-right (L-R) asymmetry. DFC proliferation defects are 26 often accompanied by impaired cilia elongation in KV, but the functional and 27 molecular interaction between cell-cycle progression and cilia formation remains 28 unknown. Here we show that chemokine receptor Cxcr4a is required for L-R laterality 29 by controlling DFC proliferation and KV ciliogenesis. Functional analysis revealed 30 that Cxcr4a accelerates G1/S transition in DFCs and stabilizes Foxj1a, a master 31 regulator of motile cilia, by stimulating Cyclin D1 expression through ERK1/2 32 signaling. Mechanistically, Cyclin D1-CDK4/6 drives G1/S transition during DFC 33 proliferation and phosphorylates Foxj1a, thereby disrupting its association with 34 Psmd4b, a 19S regulatory subunit. This prevents the ubiquitin-independent 35 proteasomal degradation of Foxj1a. Our study uncovers a role for Cxcr4 signaling in 36 L-R patterning and provides fundamental insights into the molecular linkage between 37 cell-cycle progression and ciliogenesis. 38 39 D1-CDK4/6, Foxj1a, Psmd4b, ubiquitin-independent proteasomal degradation.41 42 43 44 3 Author summary 45 During the organogenesis of zebrafish L-R organizer named KV, DFCs 46 proliferate rapidly during epiboly and then exit the cell cycle to differentiate into 47 ciliated epithelial KV cells. Cell cycle defects in DFCs are often accompanied by an 48 alteration in KV cilia elongation. However, whether the cell cycle and cilia formation 49 are mechanistically linked remains as an open question. In this study, we report that 50 Cxcr4 signaling is required for DFC proliferation and KV ciliogenesis. We reveal that 51 Cxcl12b/Cxcr4a signaling activates ERK1/2, which then promotes Cyclin D1 52 expression. Cyclin D1-CDK4/6 accelerates the G1/S transition in DFCs, while also 53 facilitates cilia formation via stabilization of Foxj1a. Notably, Foxj1 undergoes 54 proteasomal degradation via Ub-independent pathway during KV organogenesis. Our 55 study further demonstrates that CDK4 phosphorylates and stabilizes Foxj1a by 56 disrupting its association with Psmd4b, a 19S regulatory subunit. In summary, 57 Cxcl12b/Cxcr4a chemokine signaling links cell cycle progression and cilia formation 58 for L-R symmetry breaking via regulating Cyclin D1 expression. 59 60 61 62 63 64 65 66 67 Vertebrates exhibit striking left-right (L-R) asymmetries in the structure and 68 position of their cardiovascular and gastrointestinal systems. Initially, early embryos 69 develop symmetrically along the prospective body midline. This embryonic symmetry 70 is broken during somite stages when an asymmetric fluid flow is generated by motile 71 cilia within the L-R organizer (LRO), a transient structure located at the posterior end 72 of the notochord [1]. Specifically, in zebrafish, the ciliated LRO is referred to as 73 Kupffer's vesicle (KV), which ...

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Section: Resultsmentioning

confidence: 99%

Chemokine signaling links cell cycle progression and cilia formation for left-right symmetry breaking

Zhu

Guan

et al. 2019

Preprint

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“…Heterotaxia describes another rare situation (about 1:1.000), in which subsets of organs show normal or aberrant positioning and/or morphology, cases inevitably associated with severe disease syndromes [3][4][5][6] .…”

Section: Introductionmentioning

confidence: 99%

Bicc1anddicerregulate left-right patterning through post-transcriptional control of the Nodal-inhibitordand5

Maerker

Getwan

Dowdle

et al. 2020

Preprint

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Rotating cilia at the vertebrate left-right organizer (LRO) generate an asymmetric leftward flow, which is sensed by cells at the left LRO margin. How the flow signal is processed and relayed to the laterality-determining Nodal cascade in the left lateral plate mesoderm (LPM) is largely unknown. We previously showed that flow down-regulates mRNA expression of the Nodal inhibitor Dand5 in left sensory cells. De-repression of the co-expressed Nodal drives LPM Nodal cascade induction. Here, we identify the mechanism of dand5 downregulation, finding that its posttranscriptional repression is a central process in symmetry breaking. Specifically, the RNA binding protein Bicc1 interacts with a proximal element in the 3'-UTR of dand5 to repress translation in a dicer1-dependent manner. The bicc1/dicer1 module acts downstream of flow, as LRO ciliation was not affected upon its loss. Loss of bicc1 or dicer1 was rescued by parallel knockdown of dand5, placing both genes in the process of flow sensing.

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“…A similar phenotype is observed in mice mutant for the RA coactivator Rere, in which RA signaling is decreased 1 . In the viscera, bilateral coordination of the development of the two embryonic sides is altered in response to a LR signaling pathway that controls their asymmetric development 8 . In mouse and zebrafish, an Fgf8-dependent signal derived from the Node activates Nodal in the left lateral plate to specify the left embryonic identity 9–10 .…”

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confidence: 99%

“…In mouse and zebrafish, an Fgf8-dependent signal derived from the Node activates Nodal in the left lateral plate to specify the left embryonic identity 9–10 . Mutation of Fgf8 or Nodal can result in situs inversus where visceral organs become organized in a mirror-image fashion 8–10 . The right-sided somitogenesis defect observed in RA-deficient mice can be reversed by crossing them with the inversus viscerum ( iv ) mutant mice in which embryos exhibit situs inversus 7,11 .…”

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confidence: 99%

Rere-dependent Retinoic Acid signaling controls brain asymmetry and handedness

Rebagliati

Vilhais-Neto

Petiet

et al. 2019

Preprint

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While the vertebrate brain appears largely bilaterally symmetrical in humans, it presents local morphological Left-Right (LR) asymmetries as, for instance, in the petalia. Moreover, higher functions such as speech or handedness are asymmetrically localized in the cortex. How these brain asymmetries are generated remains unknown. Here, we reveal a striking parallel between the control of bilateral symmetry in the brain and in the precursors of vertebrae called somites, where a “default” asymmetry is buffered by Retinoic Acid (RA) signaling. This mechanism is evident in zebrafish and mouse and, when perturbed in both species, it translates in the brain into lateralized alterations of patterning, neuronal differentiation and behavior. We demonstrate that altering levels of the mouse RA coactivator Rere results in subtle cortex asymmetry and profoundly altered handedness, linking patterning and function in the motor cortex. Together our data uncover a novel mechanism that could underlie the establishment of brain asymmetries and handedness in vertebrates.

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Left–Right Patterning: Breaking Symmetry to Asymmetric Morphogenesis

Cited by 123 publications

References 88 publications

Chemokine signaling links cell cycle progression and cilia formation for left-right symmetry breaking

Chemokine signaling links cell cycle progression and cilia formation for left-right symmetry breaking

Bicc1anddicerregulate left-right patterning through post-transcriptional control of the Nodal-inhibitordand5

Rere-dependent Retinoic Acid signaling controls brain asymmetry and handedness

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