Modeling Human Craniofacial Disorders in Xenopus

Dubey, Aditi; Saint-Jeannet, Jean Pierre

doi:10.1007/s40139-017-0128-8

Cited by 39 publications

(36 citation statements)

References 111 publications

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“…Xenopus has proven to be an invaluable model for the study of human craniofacial development and disorders [22,[44][45][46][47][48][49][50], given the highly conserved developmental pathways that drive neural crest migration, differentiation, and craniofacial morphogenesis between systems. Nonetheless, there are gross morphological differences that prevent some direct correlations.…”

Section: Whs-associated Gene Depletion In X Laevis Almost Certainly mentioning

confidence: 99%

“…It is noteworthy that the CNC that give rise to the ceratohyal cartilage in Xenopus will later give rise to far anterior portions of the face, and combine with contributions from the Meckel's cartilage to form some regions of the jaw [51,52], but equivalent human craniofacial structures undergo distinct development [53]. Loosely, the ceratohyal cartilage in X. laevis is formed from CNC of the second PA [44,51]; which in human development will give rise to tissues of the hyoid [53]. Morphological impacts resulting from aberrant development of these tissues, as was shown with either TACC3 or WHSC2 KD (Fig.…”

Section: Whs-associated Gene Depletion In X Laevis Almost Certainly mentioning

confidence: 99%

See 1 more Smart Citation

Wolf-Hirschhorn Syndrome-associated genes are enriched in motile neural crest and affect craniofacial development inXenopus laevis

Mills

Bearce

Cella

et al. 2018

Preprint

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# These authors contributed equally to this work. Keywords craniofacial development | developmental disorders | 4p-| Wolf-Hirschhorn Syndrome | WHSC1 | WHSC2 | LETM1 | TACC3 | neural crest | disease model 1 Abstract 2 Wolf-Hirschhorn Syndrome (WHS) is a human developmental disorder arising from a 3 hemizygous perturbation, typically a microdeletion, on the short arm of chromosome four. In 4 addition to pronounced intellectual disability, seizures, and delayed growth, WHS presents with 5 a characteristic facial dysmorphism and varying prevalence of microcephaly, micrognathia, 6 40 Wolf-Hirschhorn Syndrome (WHS) is a developmental disorder characterized by intellectual 41 disability, delayed pre-and post-natal growth, heart and skeletal defects, and seizures [1-4]. A 42 common clinical marker of WHS is the "Greek Warrior Helmet" appearance; a facial pattern 43 with a characteristic wide and flattened nasal bridge, a high forehead, drastic eyebrow arches and 44 pronounced brow bones, widely spaced eyes (hypertelorism), a short philtrum, and an undersized 45 jaw (micrognathia). The majority of children with the disorder are microcephalic, and have 46 abnormally positioned ears with underdeveloped cartilage. Comorbid midline deficits can occur, 47 including cleft palate and facial asymmetries [1]. 48Craniofacial malformations make up one of the most prevalent forms of congenital defects [5,6], 49 and can significantly complicate palliative care and quality of life [7]. Given the commanding 50 role of cranial neural crest (CNC) cells in virtually all facets of craniofacial patterning, 51 craniofacial abnormalities are typically attributable to aberrant CNC development [6,8]. A 52 striking commonality in the tissues that are impacted by WHS is that a significant number derive 53 from the CNC. Despite this, little is known about how the vast diversity of genetic disruptions 54 that underlie WHS pathology can contribute to craniofacial malformation, and no study has 55 sought to characterize impacts of these genotypes explicitly on CNC behavior. 56WHS is typically caused by small, heterozygous deletions on the short-arm of chromosome 4 57 (4p16.3), which can vary widely in position and length. Initially, deletion of a very small critical 58 region, only partial segments of two genes, was thought to be sufficient for full syndromic 59 presentation [9-13]. These first putative associated genes were appropriately denoted as Wolf- 60Hirschhorn Syndrome Candidates 1 and 2 (WHSC1, WHSC2) [9,11,[14][15][16]. However, children 61 with WHS largely demonstrate 4p disruptions that impact not only this intergenic region between 62 WHSC1 and WHSC2, but instead affect multiple genes both telomeric and centromeric from this 63 locus [17]. Focus was drawn to these broader impacted regions when cases were identified that 64 neglected this first critical region entirely but still showed either full or partial WHS 65 presentation, prompting the expansion of the originally defined critical region to include a more 66 telomeric segment of ...

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Section: Whs-associated Gene Depletion In X Laevis Almost Certainly mentioning

confidence: 99%

Section: Whs-associated Gene Depletion In X Laevis Almost Certainly mentioning

confidence: 99%

Wolf-Hirschhorn Syndrome-associated genes are enriched in motile neural crest and affect craniofacial development inXenopus laevis

Mills

Bearce

Cella

et al. 2018

Preprint

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“…We developed a Xenopus model in which we could study braindependent events in embryogenesis: the brain is removed during early embryonic stages, but the animal can be kept alive and development continues. The ability of this vertebrate, a popular model for numerous biomedical contexts, [27][28][29][30][31][32][33][34] to survive and develop without a brain provides a unique opportunity to understand the role of the brain in diverse systems-level outcomes. Our prior research into brain-dependent developmental signaling revealed that the nascent brain, even before being fully formed, plays an instructive role in patterning somitic muscle and peripheral neural networks.…”

Section: Introductionmentioning

confidence: 99%

An in vivo brain–bacteria interface: the developing brain as a key regulator of innate immunity

et al. 2020

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Infections have numerous effects on the brain. However, possible roles of the brain in protecting against infection, and the developmental origin and role of brain signaling in immune response, are largely unknown. We exploited a unique Xenopus embryonic model to reveal control of innate immune response to pathogenic E. coli by the developing brain. Using survival assays, morphological analysis of innate immune cells and apoptosis, and RNA-seq, we analyzed combinations of infection, brain removal, and tail-regenerative response. Without a brain, survival of embryos injected with bacteria decreased significantly. The protective effect of the developing brain was mediated by decrease of the infection-induced damage and of apoptosis, and increase of macrophage migration, as well as suppression of the transcriptional consequences of the infection, all of which decrease susceptibility to pathogen. Functional and pharmacological assays implicated dopamine signaling in the bacteria-brain-immune crosstalk. Our data establish a model that reveals the very early brain to be a central player in innate immunity, identify the developmental origins of brain-immune interactions, and suggest several targets for immune therapies.

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“…After the induction and subsequent maintenance, NC cells migrate out of the closing neural tube to specific destinations, where they differentiate into various types of cells and contribute to many tissues, such as the craniofacial structures, dental tissues, the peripheral nervous system, pigment cells, and cardiac tissues (Bronner and Simões-Costa, 2016;Simões-Costa and Bronner, 2015;Stuhlmiller and Garcia-Castro, 2012). In humans, impaired NC development can lead to birth defects that are collectively called neurocristopathies, including craniofacial disorders, congenital heart diseases, and pigment defects (Dubey and Saint-Jeannet, 2017;Vega-Lopez et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Other common symptoms include congenital heart diseases, pigment defects, and hearing/visual impairment (Snijders Blok et al, 2015;Wang et al, 2018); a recent report also suggests that these patients have high rates of neuroblastoma, a rare NC-derived childhood tumor (Lennox et al). Because this spectrum of non-CNS symptoms is typically caused by impaired NC development (Dubey and Saint-Jeannet, 2017;Vega-Lopez et al, 2018), we hypothesized that DDX3X mutations can lead to not only CNS defects but also neurocristopathies.…”

Section: Introductionmentioning

confidence: 99%

The RNA helicase DDX3 induces neural crest by promoting AKT activity

Perfetto

Yousaf

et al. 2019

Preprint

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Mutations in the RNA helicase DDX3 have emerged as a frequent cause of intellectual disability in humans. Because many patients carrying DDX3 mutations have additional defects in craniofacial structures and other tissues containing neural crest (NC)-derived cells, we hypothesized that DDX3 is also important for NC development. Using Xenopus tropicalis as a model, we show that DDX3 is required for normal NC induction and craniofacial morphogenesis by regulating AKT kinase activity. Depletion of DDX3 decreases AKT activity and AKT-dependent inhibitory phosphorylation of GSK3b, leading to reduced levels of b-catenin and Snai1, two GSK3b substrates that are critical for NC induction. DDX3 function in regulating these downstream signaling events during NC induction is likely mediated by RAC1, a small GTPase whose translation depends on the RNA helicase activity of DDX3. These results suggest an evolutionarily conserved role of DDX3 in NC development by promoting AKT activity, and provide a potential mechanism for the NC-related birth defects displayed by patients harboring mutations in DDX3 and its downstream effectors in this signaling cascade.

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Modeling Human Craniofacial Disorders in Xenopus

Cited by 39 publications

References 111 publications

Wolf-Hirschhorn Syndrome-associated genes are enriched in motile neural crest and affect craniofacial development inXenopus laevis

Wolf-Hirschhorn Syndrome-associated genes are enriched in motile neural crest and affect craniofacial development inXenopus laevis

An in vivo brain–bacteria interface: the developing brain as a key regulator of innate immunity

The RNA helicase DDX3 induces neural crest by promoting AKT activity

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