Prickle1 regulates differentiation of frontal bone osteoblasts

Wan, Yong; Lantz, Brandi; Cusack, Brian; Szabo-Rogers, Heather L.

doi:10.1038/s41598-018-36742-0

Cited by 18 publications

(27 citation statements)

References 45 publications

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“…Our results suggest that loss of Ankrd11 predominantly affects extension of the bone via growth at the osteogenic front and bone remodeling. The frontal bone insufficiency seen in Ankrd11 ncko mice mirrors the phenotype observed in the Beetlejuice mouse, which carries a mutation in Prickle1 (Prickle1 bj/bj ) ( Wan et al, 2018 ). Prickle1 bj/bj mice also have hypoplastic frontal bones, an expanded anterior fontanelle, and frequently cleft palate.…”

Section: Discussionmentioning

confidence: 84%

“…The Prickle1 mutation is thought to affect a Wnt /Planar cell polarity ( Wnt /PCP) signaling pathway. Apoptosis and proliferation are not affected, but unlike the Ankrd11 mutant, a notable decrease in Sp7 alongside minimal changes to Runx2 expression is observed ( Wan et al, 2018 ). Mutations in core components of the Wnt /PCP pathway cause Robinow syndrome which, like KBG syndrome, results in a wider midface and shorter stature.…”

Section: Discussionmentioning

confidence: 99%

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The Chromatin Regulator Ankrd11 Controls Palate and Cranial Bone Development

Roth

Baddam

Lin

et al. 2021

Front. Cell Dev. Biol.

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Epigenetic and chromatin regulation of craniofacial development remains poorly understood. Ankyrin Repeat Domain 11 (ANKRD11) is a chromatin regulator that has previously been shown to control neural stem cell fates via modulation of histone acetylation. ANKRD11 gene variants, or microdeletions of the 16q24.3 chromosomal region encompassing the ANKRD11 gene, cause KBG syndrome, a rare autosomal dominant congenital disorder with variable neurodevelopmental and craniofacial involvement. Craniofacial abnormalities include a distinct facial gestalt, delayed bone age, tooth abnormalities, delayed fontanelle closure, and frequently cleft or submucosal palate. Despite this, the dramatic phenotype and precise role of ANKRD11 in embryonic craniofacial development remain unexplored. Quantitative analysis of 3D images of KBG syndromic subjects shows an overall reduction in the size of the middle and lower face. Here, we report that mice with heterozygous deletion of Ankrd11 in neural crest cells (Ankrd11nchet) display a mild midfacial hypoplasia including reduced midfacial width and a persistent open fontanelle, both of which mirror KBG syndrome patient facial phenotypes. Mice with a homozygous Ankrd11 deletion in neural crest cells (Ankrd11ncko) die at birth. They show increased severity of several clinical manifestations described for KBG syndrome, such as cleft palate, retrognathia, midfacial hypoplasia, and reduced calvarial growth. At E14.5, Ankrd11 expression in the craniofacial complex is closely associated with developing bony structures, while expression at birth is markedly decreased. Conditional deletion of Ankrd11 leads to a reduction in ossification of midfacial bones, with several ossification centers failing to expand and/or fuse. Intramembranous bones show features of delayed maturation, with bone remodeling severely curtailed at birth. Palatal shelves remain hypoplastic at all developmental stages, with a local reduction in proliferation at E13.5. Our study identifies Ankrd11 as a critical regulator of intramembranous ossification and palate development and suggests that Ankrd11nchet and Ankrd11ncko mice may serve as pre-clinical models for KBG syndrome in humans.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

The Chromatin Regulator Ankrd11 Controls Palate and Cranial Bone Development

Roth

Baddam

Lin

et al. 2021

Front. Cell Dev. Biol.

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“…For histological analysis, E10.5, E11.5, E15.5 embryos were collected, fixed in 4% PFA overnight, dehydrated and stored in 70% ethanol, and then embedded in paraffin wax [25]. Embryos were sectioned frontally at 10 µm and placed on triethoxysilylpropylamine (TESPA)-coated Super-Frost coated slides.…”

Section: Histology Analysismentioning

confidence: 99%

“…After washing to reduce non-specific antibody binding, the location of in situ probes were detected with BM Purple [26]. The following in situ probes were used: Alkaline phosphatase, Runx2, Sox9, Ptc1, Gli1, and Erm1 [24,25]. At least 3 littermates were analyzed per each RNA probe.…”

Section: In Situ Hybridizationmentioning

confidence: 99%

Finding the Unicorn, a New Mouse Model of Midfacial Clefting

Lantz

White

Liu

et al. 2020

Genes

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Human midfacial clefting is a rare subset of orofacial clefting and in severe cases, the cleft separates the nostrils splitting the nose into two independent structures. To begin to understand the morphological and genetic causes of midfacial clefting we recovered the Unicorn mouse line. Unicorn embryos develop a complete midfacial cleft through the lip, and snout closely modelling human midfacial clefting. The Unicorn mouse line has ethylnitrosourea (ENU)-induced missense mutations in Raldh2 and Leo1. The mutations segregate with the cleft face phenotype. Importantly, the nasal cartilages and surrounding bones are patterned and develop normal morphology, except for the lateral displacement because of the cleft. We conclude that the midfacial cleft arises from the failure of the medial convergence of the paired medial nasal prominences between E10.5 to E11.5 rather than defective cell proliferation and death. Our work uncovers a novel mouse model and mechanism for the etiology of midfacial clefting.

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“…We conducted genome-wide vQTL analyses for 20 facial measurements in 2,447 individuals. Among the suggestive vQTLs, one was located within PRICKLE1 , a gene known to contribute to the control of craniofacial development in mouse mutants ( Yang et al, 2013 ; Liu et al, 2014 ; Gibbs et al, 2016 ; Wan et al, 2018 ). We followed up on this vQTL by testing whether it interacts with other loci across the genome.…”

Section: Introductionmentioning

confidence: 99%

PRICKLE1 × FOCAD Interaction Revealed by Genome-Wide vQTL Analysis of Human Facial Traits

et al. 2021

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The human face is a highly complex and variable structure resulting from the intricate coordination of numerous genetic and non-genetic factors. Hundreds of genomic loci impacting quantitative facial features have been identified. While these associations have been shown to influence morphology by altering the mean size and shape of facial measures, their effect on trait variance remains unclear. We conducted a genome-wide association analysis for the variance of 20 quantitative facial measurements in 2,447 European individuals and identified several suggestive variance quantitative trait loci (vQTLs). These vQTLs guided us to conduct an efficient search for gene-by-gene (G × G) interactions, which uncovered an interaction between PRICKLE1 and FOCAD affecting cranial base width. We replicated this G × G interaction signal at the locus level in an additional 5,128 Korean individuals. We used the hypomorphic Prickle1Beetlejuice (Prickle1Bj) mouse line to directly test the function of Prickle1 on the cranial base and observed wider cranial bases in Prickle1Bj/Bj. Importantly, we observed that the Prickle1 and Focadhesin proteins co-localize in murine cranial base chondrocytes, and this co-localization is abnormal in the Prickle1Bj/Bj mutants. Taken together, our findings uncovered a novel G × G interaction effect in humans with strong support from both epidemiological and molecular studies. These results highlight the potential of studying measures of phenotypic variability in gene mapping studies of facial morphology.

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Prickle1 regulates differentiation of frontal bone osteoblasts

Cited by 18 publications

References 45 publications

The Chromatin Regulator Ankrd11 Controls Palate and Cranial Bone Development

The Chromatin Regulator Ankrd11 Controls Palate and Cranial Bone Development

Finding the Unicorn, a New Mouse Model of Midfacial Clefting

PRICKLE1 × FOCAD Interaction Revealed by Genome-Wide vQTL Analysis of Human Facial Traits

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