Cell non-autonomy amplifies disruption of neurulation by mosaic Vangl2 deletion in mice

Galea, Gabriel L.; Maniou, Eirini; Edwards, Timothy J.; Marshall, Abigail R.; Ampartzidis, Ioakeim; Greene, Nicholas D. E.; Copp, Andrew J.

doi:10.1038/s41467-021-21372-4

Cited by 31 publications

(40 citation statements)

References 113 publications

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“…However, the biological mechanisms underlying this developmental anomaly and associated cutaneous stigmata are not well understood and may be under-reported due to inherent challenges in resolving these genetic events. Post-zygotic variation, including single nucleotide changes and copy number alteration, has been described in planar cell polarity genes in association with open neural tube defects (Tian et al 2020;Galea et al 2021). Such findings support that somatic mosaicism may serve as a mechanism of disease.…”

Section: Discussionmentioning

confidence: 65%

Expanding the Clinical Phenotype of FGFR1 Internal Tandem Duplication

Kautto

Schieffer

McGrath

et al. 2022

Cold Spring Harb Mol Case Stud

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Closed spinal dysraphism (SD) is a type of neural tube defect originating during early embryonic development whereby the neural tissue of the spinal defect remains covered by skin, often coinciding with markers of cutaneous stigmata. It is hypothesized that these events are caused by multifactorial processes, including genetic and environmental causes. We present an infant with a unique congenital midline lesion associated with a closed SD. Through comprehensive molecular profiling of the intraspinal lesion and contiguous skin lesion, an internal tandem duplication (ITD) of the kinase domain of the fibroblast growth factor receptor 1 (FGFR1) gene was found. Absence of this event in the peripheral blood and deviation of a variant allele frequency from a heterozygous state suggests that this event is somatic mosaic in nature. FGFR1 ITD results in constitutive activation of the receptor tyrosine kinase to promote cell growth, differentiation, and survival through RAS/MAPK signaling. Identification of FGFR1 ITD outside of central nervous system tumors is exceedingly rare.

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Section: Discussionmentioning

confidence: 65%

Expanding the Clinical Phenotype of FGFR1 Internal Tandem Duplication

Kautto

Schieffer

McGrath

et al. 2022

Cold Spring Harb Mol Case Stud

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“…With respect to congenital abnormalities such as NTDs, the existing literature concerning any association between somatic variants with the development of an NTD is quite limited. Galea et al (2018Galea et al ( , 2021 reported that a somatic Vangl2 deletion in murine neuroepithelial cells as well as in surface ectodermal cells causes SB in mice. In our recent publication, we described somatic variants in some key PCP genes (e.g., VANGL1 and FZD6) in neural tissue that are associated with human NTDs, suggesting a potentially important role somatic variants can play in the occurrence of human NTDs (Tian et al, 2021).…”

Section: Human Ntd Associated Gene Variants Can Be Germline or Somaticmentioning

confidence: 99%

Unraveling the complex genetics of neural tube defects: From biological models to human genomics and back

Wolujewicz

Steele

Kaltschmidt

et al. 2021

Genesis

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Neural tube defects (NTDs) are a classic example of preventable birth defects for which there is a proven‐effective intervention, folic acid (FA); however, further methods of prevention remain unrealized. In the decades following implementation of FA nutritional fortification programs throughout at least 87 nations, it has become apparent that not all NTDs can be prevented by FA. In the United States, FA fortification only reduced NTD rates by 28–35% (Williams et al., 2015). As such, it is imperative that further work is performed to understand the risk factors associated with NTDs and their underlying mechanisms so that alternative prevention strategies can be developed. However, this is complicated by the sheer number of genes associated with neural tube development, the heterogeneity of observable phenotypes in human cases, the rareness of the disease, and the myriad of environmental factors associated with NTD risk. Given the complex genetic architecture underlying NTD pathology and the way in which that architecture interacts dynamically with environmental factors, further prevention initiatives will undoubtedly require precision medicine strategies that utilize the power of human genomics and modern tools for assessing genetic risk factors. Herein, we review recent advances in genomic strategies for discovering genetic variants associated with these defects, and new ways in which biological models, such as mice and cell culture‐derived organoids, are leveraged to assess mechanistic functionality, the way these variants interact with other genetic or environmental factors, and their ultimate contribution to human NTD risk.

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“…Closure is a complex, coordinated, dynamic process in which active multi-scale cell-generated forces exceed residual tissue stresses to produce tubular morphogenesis (6)(7)(8)(9). Genetic or teratogenic disruptions of neural tube closure biomechanics can cause neural tube defects (10,11). Although essential, the analysis of morphogenetic forces generated during vertebrate neural tube closure has not yet been possible.…”

Section: Introductionmentioning

confidence: 99%

Quantifying mechanical forces during vertebrate morphogenesis

Elvassore

Maniou²,

Todros

et al. 2022

Preprint

Self Cite

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Morphogenesis, the establishment of rudimentary organ structures, requires embryonic cells to generate forces and perform mechanical work to shape their tissues. Incorrect functioning of these force fields can lead to congenital malformations including neural tube defects. The understanding of these dynamic processes requires quantification and profiling of three-dimensional mechanics during evolving vertebrate morphogenesis, which is not tractable with current technology. We fabricated elastic spring-like force sensors with micron-level resolution directly into specific three-dimensional domains of the closing neural tubes of growing chicken embryos through intravital three-dimensional bioprinting. Integration of calibrated sensor readouts with computational mechanical modelling allows direct quantification of forces and work performed by embryonic tissues. The two halves of the closing neural tube at the embryonic midline reach over a hundred nano-Newton compression during neural fold apposition. Unexpectedly, diminishing pro-closure force by pharmacologically inhibiting Rho-associated kinase reveals active anti-closure forces which must depend on alternative mechanisms or tissue properties, and which progressively widen the neural tube. Pro-morphogenetic forces must therefore overcome anti-morphogenetic forces to achieve neural tube closure.

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Cell non-autonomy amplifies disruption of neurulation by mosaic Vangl2 deletion in mice

Cited by 31 publications

References 113 publications

Expanding the Clinical Phenotype of FGFR1 Internal Tandem Duplication

Expanding the Clinical Phenotype of FGFR1 Internal Tandem Duplication

Unraveling the complex genetics of neural tube defects: From biological models to human genomics and back

Quantifying mechanical forces during vertebrate morphogenesis

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