scholarly journals Embryonic requirements for Tcf12 in the development of the mouse coronal suture

Development ◽  
2021 ◽  
Author(s):  
Man-chun Ting ◽  
D'Juan T. Farmer ◽  
Camilla S. Teng ◽  
Jinzhi He ◽  
Yang Chai ◽  
...  

A major feature of Saethre-Chotzen syndrome is coronal craniosynostosis, the fusion of the frontal and parietal bones at the coronal suture. It is caused by heterozygous loss-of-function mutations in either of the basic HLH transcription factors TWIST1 and TCF12. While compound heterozygous Tcf12; Twist1 mice display severe coronal synostosis, the individual role of Tcf12 had remained unexplored. Here we show that Tcf12 controls several key processes in calvarial development, including the rate of frontal and parietal bone growth, and the boundary between sutural and osteogenic cells. Genetic analysis supports an embryonic requirement for Tcf12 in suture formation, as combined deletion of Tcf12 in embryonic neural crest and mesoderm, but not in postnatal suture mesenchyme, disrupts the coronal suture. We also detect asymmetric distribution of mesenchymal cells on opposing sides of the wild-type frontal and parietal bones, which prefigures later bone overlap at the sutures. In Tcf12 mutants, reduced asymmetry is associated with bones meeting end-on-end, possibly contributing to synostosis. Our results support embryonic requirements of Tcf12 in proper formation of the overlapping coronal suture.

2021 ◽  
Author(s):  
Man-chun Ting ◽  
D’Juan T. Farmer ◽  
Camilla S. Teng ◽  
Jinzhi He ◽  
Yang Chai ◽  
...  

AbstractA major feature of Saethre-Chotzen syndrome is coronal craniosynostosis, the fusion of the frontal and parietal bones at the coronal suture. It is caused by heterozygous loss-of-function mutations in the basic HLH transcription factorsTWIST1andTCF12. While compound heterozygousTcf12; Twist1mice display severe coronal synostosis, the individual role ofTcf12has remained unexplored. Here we show that Tcf12 controls several key processes in calvarial development, including the rate of frontal and parietal bone growth, and the boundary between sutural and osteogenic cells. Genetic analysis supports an embryonic requirement forTcf12in suture formation, as combined deletion ofTcf12in the embryonic neural crest and mesoderm, but not in the postnatal suture mesenchyme, disrupts the coronal suture. We also detect asymmetric distribution of Grem1 + mesenchymal cells on opposing sides of the wild-type frontal and parietal bones, which prefigures later bone overlap at the sutures. InTcf12mutants, reduced asymmetry correlates with lack of bone overlap. Our results indicate a largely embryonic function of Tcf12 in controlling the rate and asymmetrical growth of calvarial bones and establishment of suture boundaries, which together ensure the proper formation of the overlapping coronal suture.


Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1240
Author(s):  
Agnieszka Rafalska ◽  
Anna M. Tracewska ◽  
Anna Turno-Kręcicka ◽  
Milena J. Szafraniec ◽  
Marta Misiuk-Hojło

CEP290 is a ciliary gene frequently mutated in ciliopathies, resulting in a broad range of phenotypes, ranging from isolated inherited retinal disorders (IRDs) to severe or lethal syndromes with multisystemic involvement. Patients with non-syndromic CEP290-linked disease experience profound and early vision loss due to cone-rod dystrophy, as in Leber congenital amaurosis. In this case report, we describe two novel loss-of-function heterozygous alterations in the CEP290 gene, discovered in a patient suffering from retinitis pigmentosa using massive parallel sequencing of a molecular inversion probes library constructed for 108 genes involved in IRDs. A milder phenotype than expected was found in the individual, which serves to prove that some CEP290-associated disorders may display preserved cone function.


2013 ◽  
Vol 6 (2) ◽  
pp. 115-120 ◽  
Author(s):  
Han J. Choi ◽  
Rohana K. De Silva ◽  
Darryl C. Tong ◽  
Harsha L. De Silva ◽  
Robert M. Love ◽  
...  

ObjectivesTo evaluate the average thickness of the parietal bones in their different regions to identify the ideal site(s) for calvarial bone graft harvest.Methods and MaterialsThickness of the parietal bones of 25 wet cranial vaults of New Zealand European origin was measured in 135 different locations using an electronic caliper. Analyses to identify the ideal harvest sites were conducted so that the sites fit the features of an ideal harvest site described in the literature as: (1) 6 mm of minimum thickness and (2) 2 cm away from the midline.Results and ConclusionThe overall average thickness was 6.69 ± 0.22 mm. The average thickness at different sites within the same bone ranged from 2.85 to 6.93 mm. In keeping with previous studies, the report observed a progressive thickening of the parietal bone in medial and posterior directions. Of the 135 different locations measured, only 20% exceeded an average thickness of 6 mm as well as being 2 cm away from the sagittal midline. These locations were mainly located between 6 to 11 cm posterior to the coronal suture and 2 to 5 cm away from the sagittal suture.ConclusionHarvesting the calvarial bone graft in the area 6 to 11 cm posterior to the coronal suture and 2 cm away from the midline is recommended based on our study using cadaveric cranial vaults of New Zealand Europeans.


eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Camilla S Teng ◽  
Man-chun Ting ◽  
D'Juan T Farmer ◽  
Mia Brockop ◽  
Robert E Maxson ◽  
...  

Cranial sutures separate the skull bones and house stem cells for bone growth and repair. In Saethre-Chotzen syndrome, mutations in TCF12 or TWIST1 ablate a specific suture, the coronal. This suture forms at a neural-crest/mesoderm interface in mammals and a mesoderm/mesoderm interface in zebrafish. Despite this difference, we show that combinatorial loss of TCF12 and TWIST1 homologs in zebrafish also results in specific loss of the coronal suture. Sequential bone staining reveals an initial, directional acceleration of bone production in the mutant skull, with subsequent localized stalling of bone growth prefiguring coronal suture loss. Mouse genetics further reveal requirements for Twist1 and Tcf12 in both the frontal and parietal bones for suture patency, and to maintain putative progenitors in the coronal region. These findings reveal conservation of coronal suture formation despite evolutionary shifts in embryonic origins, and suggest that the coronal suture might be especially susceptible to imbalances in progenitor maintenance and osteoblast differentiation.


2021 ◽  
Author(s):  
D’Juan T. Farmer ◽  
Hana Mlcochova ◽  
Yan Zhou ◽  
Nils Koelling ◽  
Guanlin Wang ◽  
...  

AbstractSutures separate the flat bones of the skull and enable coordinated growth of the brain and overlying cranium. To uncover the cellular diversity within sutures, we generated single-cell transcriptomes and performed extensive expression validation of the embryonic murine coronal suture. We identify Erg and Pthlh as markers of osteogenic progenitors in sutures, and distinct pre-osteoblast signatures between the bone fronts and periosteum. In the ectocranial layers above the suture, we observe a ligament-like population spanning the frontal and parietal bones. In the dura mater underlying the suture, we detect a chondrocyte-like signature potentially linked to cartilage formation under pathological conditions. Genes mutated in coronal synostosis are preferentially expressed in proliferative osteogenic cells, as well as meningeal layers, suggesting discrete cell types that may be altered in different syndromes. This single-cell atlas provides a resource for understanding development of the coronal suture, the suture most commonly fused in monogenic craniosynostosis.


2021 ◽  
Author(s):  
D'Juan Farmer ◽  
Hana Mlcochova ◽  
Yan Zhou ◽  
Nils Koelling ◽  
Guanlin Wang ◽  
...  

Abstract Sutures separate the flat bones of the skull and enable coordinated growth of the brain and overlying cranium. To uncover the cellular diversity within sutures, we generated single-cell transcriptomes and performed extensive expression validation of the embryonic murine coronal suture. We identify Erg and Pthlh as markers of osteogenic progenitors in sutures, and distinct pre-osteoblast signatures between the bone fronts and periosteum. In the ectocranial layers above the suture, we observe a ligament-like population spanning the frontal and parietal bones. In the dura mater underlying the suture, we detect a chondrocyte-like signature potentially linked to cartilage formation under pathological conditions. Genes mutated in coronal synostosis are preferentially expressed in proliferative osteogenic cells, as well as meningeal layers, suggesting discrete cell types that may be altered in different syndromes. This single-cell atlas provides a resource for understanding development of the coronal suture, the suture most commonly fused in monogenic craniosynostosis.


Medicina ◽  
2021 ◽  
Vol 57 (2) ◽  
pp. 123
Author(s):  
Cigdem Yuce Kahraman ◽  
Ali Islek ◽  
Abdulgani Tatar ◽  
Özlem Özdemir ◽  
Adil Mardinglu ◽  
...  

Wilson disease (WD) (OMIM# 277900) is an autosomal recessive inherited disorder characterized by excess copper (Cu) storage in different human tissues, such as the brain, liver, and the corneas of the eyes. It is a rare disorder that occurs in approximately 1 in 30,000 individuals. The clinical presentations of WD are highly varied, primarily consisting of hepatic and neurological conditions. WD is caused by homozygous or compound heterozygous mutations in the ATP7B gene. The diagnosis of the disease is complicated because of its heterogeneous phenotypes. The molecular genetic analysis encourages early diagnosis, treatment, and the opportunity to screen individuals at risk in the family. In this paper, we reported a case with a novel, hotspot-located mutation in WD. We have suggested that this mutation in the ATP7B gene might contribute to liver findings, progressing to liver failure with a loss of function effect. Besides this, if patients have liver symptoms in childhood and/or are children of consanguineous parents, WD should be considered during the evaluation of the patients.


Neurosurgery ◽  
2010 ◽  
Vol 67 (3) ◽  
pp. 663-674 ◽  
Author(s):  
Kartik G. Krishnan ◽  
Gabriele Schackert ◽  
Volker Seifert

Abstract BACKGROUND The functions of the human face are not only of esthetic significance but also extend into metaphoric nuances of psychology. The loss of function of one or both facial nerves has a remarkable impact on patients' lives. OBJECTIVE To retrospectively analyze the functional outcomes of microneurovascular facial reanimation using masseteric innervation. METHODS Seventeen patients with irreparable facial paralysis resulting from benign lesions involving the facial nuclei (n = 14) or Möbius syndrome (n = 3) were treated with free muscle flaps for oral commissural reanimation using ipsilateral masseteric innervation and using temporalis muscle transfer for eyelid reanimation. Results were analyzed by the absolute commissural excursion and commissural excursion index and by a patient self-evaluation score. Presence of synkinesis was documented. Follow-up ranged from 8 to 48 months (mean, 26.4 months). RESULTS Normalization of the commissural excursion index was observed in 8 of 17 patients (47%), an improvement was seen in 7 of 17 (41%), and failure was observed in 2 of 17 (12%). The individual dynamics of absolute commissural excursion and commissural excursion index changes are presented. A natural smiling response was observed in 10 of 17 patients (59%) but not in the remaining 7 (41%). This response reflected the patient's ability to relay the natural emotion of smiling through the masseteric nerve. Patients' self-evaluation scores were a level higher than objective indices. CONCLUSIONS Innervation of free muscle flaps with the masseteric nerve for oral commissure reanimation might play an important role in patients with lesions of the facial nuclei (as in Möbius syndrome). Synkinesis persists for long periods after surgery. However, most of the patients learned to express their emotions by overcoming this phenomenon. Despite hypercorrection or inadequate correction, patients evaluated themselves favorably.


Author(s):  
Annika Winbo ◽  
Suganeya Ramanan ◽  
Emily Eugster ◽  
Annika Rydberg ◽  
Stefan Jovinge ◽  
...  

Sympathetic activation is an established trigger of life-threatening cardiac events in long QT syndrome type 1 (LQT1). KCNQ1 loss-of-function variants, which underlie LQT1, have been associated with both cardiac arrhythmia and neuronal hyperactivity pathologies. However, the LQT1 sympathetic neuronal phenotype is unknown. Here we aimed to study human induced pluripotent stem cell (hiPSC)-derived sympathetic neurons (SNs) to evaluate neuronal functional phenotype in LQT1. We generated hiPSC-SNs from two LQT1 patients with a history of sympathetically triggered arrhythmia and KCNQ1 loss-of-function genotypes (c.781_782delinsTC and p.S349W/p.R518X). Characterisation of hiPSC-SNs was performed using immunohistochemistry, enzyme-linked immunosorbent assay and whole-cell patch clamp electrophysiology, and functional LQT1 hiPSC-SN phenotypes compared to healthy control (WT) hiPSC-SNs. hiPSC-SNs stained positive for tyrosine hydroxylase, peripherin, KCNQ1, and secreted noradrenaline. hiPSC-SNs at 60±2.2 days in vitro had healthy resting membrane potentials (-60±1.3 mV), and fired rapid action potentials with mature kinetics in response to stimulation. Significant hyperactivity in LQT1 hiPSC-SNs was evident via increased noradrenaline release, increased spontaneous action potential frequency, increased total inward current density, and reduced afterhyperpolarisation, compared to age-matched WT hiPSC-SNs. A significantly higher action potential frequency upon current injection and larger synaptic current amplitudes in compound heterozygous p.S349W/p.R518X hiPSC-SNs compared to heterozygous c.781_782delinsTC hiPSC-SNs was also observed, suggesting a potential genotype-phenotype correlation. Together our data reveal increased neurotransmission and excitability in heterozygous and compound heterozygous patient-derived LQT1 sympathetic neurons, suggesting that the cellular arrhythmogenic potential in LQT1 is not restricted to cardiomyocytes.


Author(s):  
Pradeep Vasudevan ◽  
Corrina Powell ◽  
Adeline K Nicholas ◽  
Ian Scudamore ◽  
James Greening ◽  
...  

Summary In the absence of maternal thyroid disease or iodine deficiency, fetal goitre is rare and usually attributable to dyshormonogenesis, for which genetic ascertainment is not always undertaken in the UK. Mechanical complications include tracheal and oesophageal compression with resultant polyhydramnios, malpresentation at delivery and neonatal respiratory distress. We report an Indian kindred in which the proband (first-born son) had congenital hypothyroidism (CH) without obvious neonatal goitre. His mother’s second pregnancy was complicated by fetal hypothyroid goitre and polyhydramnios, prompting amniotic fluid drainage and intraamniotic therapy (with liothyronine, T3 and levothyroxine, T4). Sadly, intrauterine death occurred at 31 weeks. Genetic studies in the proband demonstrated compound heterozygous novel (c.5178delT, p.A1727Hfs*26) and previously described (c.7123G > A, p.G2375R) thyroglobulin (TG) mutations which are the likely cause of fetal goitre in the deceased sibling. TG mutations rarely cause fetal goitre, and management remains controversial due to the potential complications of intrauterine therapy however an amelioration in goitre size may be achieved with intraamniotic T4, and intraamniotic T3/T4 combination has achieved a favourable outcome in one case. A conservative approach, with surveillance, elective delivery and commencement of levothyroxine neonatally may also be justified, although intubation may be required post delivery for respiratory obstruction. Our observations highlight the lethality which may be associated with fetal goitre. Additionally, although this complication may recur in successive pregnancies, our case highlights the possibility of discordance for fetal goitre in siblings harbouring the same dyshormonogenesis-associated genetic mutations. Genetic ascertainment may facilitate prenatal diagnosis and assist management in familial cases. Learning points: CH due to biallelic, loss-of-function TG mutations is well-described and readily treatable in childhood however mechanical complications from associated fetal goitre may include polyhydramnios, neonatal respiratory compromise and neck hyperextension with dystocia complicating delivery. CH due to TG mutations may manifest with variable phenotypes, even within the same kindred. Treatment options for hypothyroid dyshormogenic fetal goitre in a euthyroid mother include intraamniotic thyroid hormone replacement in cases with polyhydramnios or significant tracheal obstruction. Alternatively, cases may be managed conservatively with radiological surveillance, elective delivery and neonatal levothyroxine treatment, although intubation and ventilation may be required to support neonatal respiratory compromise. Genetic ascertainment in such kindreds may enable prenatal diagnosis and anticipatory planning for antenatal management of further affected offspring.


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