Mechanistic insights from the LHX1‐driven molecular network in building the embryonic head

McMahon, Riley; Sibbritt, Tennille; Salehin, Nazmus; Osteil, Pierre; Tam, Patrick

doi:10.1111/dgd.12609

Cited by 14 publications

(11 citation statements)

References 89 publications

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“…These syndromes are associated with a range of mental and physical disabilities as well as craniofacial abnormalities. We screened several candidate genes located in these regions that are involved in craniofacial development, such as PCYT1A (3q29), [15], DLG1 (3q29), [16]), and LHX1 (17q12), [17,18]. Although TBX6 is considered to be a key gene resulting in several major phenotypes in 16p11.2 duplication, potential genes associated with orofacial cleft in this region still require further exploration.…”

Section: Discussionmentioning

confidence: 99%

Clinical application of chromosomal microarray analysis for fetuses with craniofacial malformations

Xiang

et al. 2020

Mol Cytogenet

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Background: The potential correlations between chromosomal abnormalities and craniofacial malformations (CFMs) remain a challenge in prenatal diagnosis. This study aimed to evaluate 118 fetuses with CFMs by applying chromosomal microarray analysis (CMA) and G-banded chromosome analysis. Results: Of the 118 cases in this study, 39.8% were isolated CFMs (47/118) whereas 60.2% were non-isolated CFMs (71/118). The detection rate of chromosomal abnormalities in non-isolated CFM fetuses was significantly higher than that in isolated CFM fetuses (26/71 vs. 7/47, p = 0.01). Compared to the 16 fetuses (16/104; 15.4%) with pathogenic chromosomal abnormalities detected by karyotype analysis, CMA identified a total of 33 fetuses (33/118; 28.0%) with clinically significant findings. These 33 fetuses included cases with aneuploidy abnormalities (14/118; 11.9%), microdeletion/microduplication syndromes (9/118; 7.6%), and other pathogenic copy number variations (CNVs) only (10/118; 8.5%).We further explored the CNV/phenotype correlation and found a series of clear or suspected dosage-sensitive CFM genes including TBX1, MAPK1, PCYT1A, DLG1, LHX1, SHH, SF3B4, FOXC1, ZIC2, CREBBP, SNRPB, and CSNK2A1. Conclusion: These findings enrich our understanding of the potential causative CNVs and genes in CFMs. Identification of the genetic basis of CFMs contributes to our understanding of their pathogenesis and allows detailed genetic counselling.

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Section: Discussionmentioning

confidence: 99%

Clinical application of chromosomal microarray analysis for fetuses with craniofacial malformations

Xiang

et al. 2020

Mol Cytogenet

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“…To examine the zli , we investigated LIM homeobox 1 ( lhx1 ), a transcription factor known to regulate differentiation and morphogenetic tissue movement in head development [ 68 – 71 ]. In both mice and Xenopus, lhx1 depletion leads to loss of anterior head structures [ 68 , 72 ] and is known to be expressed in the zli. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

In Xenopus ependymal cilia drive embryonic CSF circulation and brain development independently of cardiac pulsatile forces

Dur

Tang

Viviano

et al. 2020

Fluids Barriers CNS

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Background Hydrocephalus, the pathological expansion of the cerebrospinal fluid (CSF)-filled cerebral ventricles, is a common, deadly disease. In the adult, cardiac and respiratory forces are the main drivers of CSF flow within the brain ventricular system to remove waste and deliver nutrients. In contrast, the mechanics and functions of CSF circulation in the embryonic brain are poorly understood. This is primarily due to the lack of model systems and imaging technology to study these early time points. Here, we studied embryos of the vertebrate Xenopus with optical coherence tomography (OCT) imaging to investigate in vivo ventricular and neural development during the onset of CSF circulation. Methods Optical coherence tomography (OCT), a cross-sectional imaging modality, was used to study developing Xenopus tadpole brains and to dynamically detect in vivo ventricular morphology and CSF circulation in real-time, at micrometer resolution. The effects of immobilizing cilia and cardiac ablation were investigated. Results In Xenopus, using OCT imaging, we demonstrated that ventriculogenesis can be tracked throughout development until the beginning of metamorphosis. We found that during Xenopus embryogenesis, initially, CSF fills the primitive ventricular space and remains static, followed by the initiation of the cilia driven CSF circulation where ependymal cilia create a polarized CSF flow. No pulsatile flow was detected throughout these tailbud and early tadpole stages. As development progressed, despite the emergence of the choroid plexus in Xenopus, cardiac forces did not contribute to the CSF circulation, and ciliary flow remained the driver of the intercompartmental bidirectional flow as well as the near-wall flow. We finally showed that cilia driven flow is crucial for proper rostral development and regulated the spatial neural cell organization. Conclusions Our data support a paradigm in which Xenopus embryonic ventriculogenesis and rostral brain development are critically dependent on ependymal cilia-driven CSF flow currents that are generated independently of cardiac pulsatile forces. Our work suggests that the Xenopus ventricular system forms a complex cilia-driven CSF flow network which regulates neural cell organization. This work will redirect efforts to understand the molecular regulators of embryonic CSF flow by focusing attention on motile cilia rather than other forces relevant only to the adult.

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“…These syndromes are associates with a range of mental and physical disabilities as well as craniofacial abnormalities. We screened several candidate genes located in these regions involved in craniofacial development, such as PCYT1A (locus 3q29) [18], DLG1 (locus 3q29) [19], and LHX1 (locus 17q12) [20,21]. Although TBX6 is considered to be a key gene that results in several major phenotypes in 16p11.2 duplication, potential genes associated with orofacial cleft of this region still need further exploration.…”

Section: Discussionmentioning

confidence: 99%

Clinical Application of Chromosomal Microarray Analysis for Fetuses with Craniofacial Malformations

Xiang

et al. 2020

Preprint

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Background This study aimed to evaluate the applicability of chromosomal microarray analysis (CMA) for prenatal diagnosis of craniofacial malformations (CFMs). We also investigated the potential correlations between chromosomal abnormalities and CFMs. To this end, 118 fetuses with CFMs were enrolled in the study and underwent both G-banded chromosome analysis and CMA. Results Of the 118 cases in this study, 39.8% were isolated CFMs (47/118) whereas 60.2% were non-isolated CFMs (71/118). The detection rate of chromosomal abnormalities or submicroscopic chromosomal abnormalities in non-isolated CFM fetuses was significantly higher than that in isolated CFM fetuses (26/71 vs. 7/47, p = 0.01). Compared to the 16 fetuses (16/104; 15.4%) with pathogenic chromosomal abnormalities detected by karyotype analysis, CMA identified a total of 33 fetuses (33/118; 28.0%) with clinically significant findings. These 33 fetuses included cases with aneuploidy abnormalities (14/118; 11.9%), microdeletion/microduplication syndromes (9/118; 7.6%), and other pathogenic CNVs only (10/118; 8.5%). We further explored the CNV/phenotype correlation and found a series of clear or suspected dosage-sensitive CFM genes. Conclusion CMA is a rapid and reliable molecular technique to identify fetal chromosomal aberrations associated with CFMs. Identification of the genetic basis of CFMs contributes to the understanding of their pathogenesis and etiology.

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Mechanistic insights from the LHX1‐driven molecular network in building the embryonic head

Cited by 14 publications

References 89 publications

Clinical application of chromosomal microarray analysis for fetuses with craniofacial malformations

Clinical application of chromosomal microarray analysis for fetuses with craniofacial malformations

In Xenopus ependymal cilia drive embryonic CSF circulation and brain development independently of cardiac pulsatile forces

Clinical Application of Chromosomal Microarray Analysis for Fetuses with Craniofacial Malformations

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