Mouse Dspp frameshift model of human dentinogenesis imperfecta

Liang, Tian; Hu, Yuanyuan; Zhang, Hong; Xu, Quanhua; Smith, Charles E.; Zhang, Chuhua; Kim, Jung-Wook; Wang, Shih‐Kai; Saunders, Thomas L.; Lu, Yongbo; Hu, Jan C.‐C.; Simmer, James P.

doi:10.1038/s41598-021-00219-4

Cited by 13 publications

(19 citation statements)

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“…Previously we generated two Dspp -knockin mouse models: Dspp P19L mice 12 homologous to the p.Pro17Leu mutation in humans 6 , 13 – 15 representing the 5’ group of DSPP mutations, and Dspp −1fs mice 16 representing the 3’ group of human DSPP -1 frameshift mutations. Both mice displayed dental defects inherited in an autosomal dominant pattern and showed intracellular accumulation of mutated DSPP but varied in their dental phenotypes and cell abnormalities.…”

Section: Introductionmentioning

confidence: 99%

“…In this respect the odontoblast response resembles the formation of reactionary dentin 17 . The enamel shows reduced mineral density in incisors and patches of enamel dysplasia in molars 16 , 18 , indicating that ameloblast were altered by their transient expression of the mutated DSPP protein.…”

Section: Introductionmentioning

confidence: 99%

“…Dentin defects in Dspp −1fs mice are more severe than those in the Dspp P19L mice, with limited dentin deposition and the absence of dentinal tubules. The original odontoblasts do not long survive the expression of the frameshifted DSPP and are replaced by pulp progenitor cells that initiate expression of dentin matrix protein 1 (DMP1), a marker expressed by differentiating odontoblasts 16 . These cells undergo an apparent cycling of -1 frameshifted DSPP expression, cell death, and induction of pulp progenitor cells that express the -1 frameshifted DSPP.…”

Section: Introductionmentioning

confidence: 99%

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Dentin defects caused by a Dspp−1 frameshift mutation are associated with the activation of autophagy

Liang

Smith

et al. 2023

Sci Rep

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Dentin sialophosphoprotein (DSPP) is primarily expressed by differentiated odontoblasts (dentin-forming cells), and transiently expressed by presecretory ameloblasts (enamel-forming cells). Disease-causing DSPP mutations predominantly fall into two categories: 5’ mutations affecting targeting and trafficking, and 3’ − 1 frameshift mutations converting the repetitive, hydrophilic, acidic C-terminal domain into a hydrophobic one. We characterized the dental phenotypes and investigated the pathological mechanisms of DsppP19L and Dspp−1fs mice that replicate the two categories of human DSPP mutations. In DsppP19L mice, dentin is less mineralized but contains dentinal tubules. Enamel mineral density is reduced. Intracellular accumulation and ER retention of DSPP is observed in odontoblasts and ameloblasts. In Dspp−1fs mice, a thin layer of reparative dentin lacking dentinal tubules is deposited. Odontoblasts show severe pathosis, including intracellular accumulation and ER retention of DSPP, strong ubiquitin and autophagy activity, ER-phagy, and sporadic apoptosis. Ultrastructurally, odontoblasts show extensive autophagic vacuoles, some of which contain fragmented ER. Enamel formation is comparable to wild type. These findings distinguish molecular mechanisms underlying the dental phenotypes of DsppP19L and Dspp−1fs mice and support the recently revised Shields classification of dentinogenesis imperfecta caused by DSPP mutations in humans. The Dspp−1fs mice may be valuable for the study of autophagy and ER-phagy.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dentin defects caused by a Dspp−1 frameshift mutation are associated with the activation of autophagy

Liang

Smith

et al. 2023

Sci Rep

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“…Due to the gestational time period of dental patterning and morphogenesis (42)(43)(44)(45)(46) and lack of clear human in vitro models, tooth development is primarily studied using mice. The early stages of development of the mouse dentition are largely morphologically and molecularly analogous to human dental development (42)(43)(44), and many rare human dental syndromes are modelable in mice (42,44,(47)(48)(49). While a group has previously identified a region upstream of Shh whose disruption demonstrates a dental phenotype in mice, systematic characterization of the activity of the noncoding genome in the developing tooth of mammals has not been performed (35,50).…”

Section: Introductionmentioning

confidence: 99%

Integration of multimodal data in the developing tooth reveals candidate regulatory loci driving human odontogenic phenotypes

Winchester

Cotney

2022

Front. Dent. Med

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Human odontogenic aberrations such as abnormal tooth number and delayed tooth eruption can occur as a symptom of rare syndromes or, more commonly, as nonsyndromic phenotypes. These phenotypes can require extensive and expensive dental treatment, posing a significant burden. While many dental phenotypes are heritable, most nonsyndromic cases have not been linked to causal genes. We demonstrate the novel finding that common sequence variants associated with human odontogenic phenotypes are enriched in developmental craniofacial enhancers conserved between human and mouse. However, the bulk nature of these samples obscures if this finding is due to the tooth itself or the surrounding tissues. We therefore sought to identify enhancers specifically active in the tooth anlagen and quantify their contribution to the observed genetic enrichments. We systematically identified 22,001 conserved enhancers active in E13.5 mouse incisors using ChIP-seq and machine learning pipelines and demonstrated biologically relevant enrichments in putative target genes, transcription factor binding motifs, and in vivo activity. Multi-tissue comparisons of human and mouse enhancers revealed that these putative tooth enhancers had the strongest enrichment of odontogenic phenotype-associated variants, suggesting a role for dysregulation of tooth developmental enhancers in human dental phenotypes. The large number of these regions genome-wide necessitated prioritization of enhancer loci for future investigations. As enhancers modulate gene expression, we prioritized regions based on enhancers' putative target genes. We predicted these target genes and prioritized loci by integrating chromatin state, bulk gene expression and coexpression, GWAS variants, and cell type resolved gene expression to generate a prioritized list of putative odontogenic phenotype-driving loci active in the developing tooth. These genomic regions are of particular interest for downstream experiments determining the role of specific dental enhancer:gene pairs in odontogenesis.

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“…The early stages of development of the mouse dentition are largely analogous to human dental development [42][43][44], and many rare human dental syndromes are modelable in mice. [42,44,[47][48][49] However, investigations into the noncoding genome of the developing tooth in mammals have been limited to a small number of regions [50,51]. As such, the conservation of the noncoding drivers of dental development between human and mouse genome-wide has not been definitively proven.…”

Section: Introductionmentioning

confidence: 99%

“Integration of multimodal data in the developing tooth reveals candidate dental disease genes”

Winchester

Cotney

2022

Preprint

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Dental malformations and diseases affect a large number of people in their lifetime. Their widespread occurrence and the documented influence of oral health on systemic health make understanding their risk factors a public health priority. Previous studies have shown that common dental phenotypes are heritable, but the genetic causes of most cases have not been identified. Loci that harbor risk for human craniofacial morphology and related diseases are enriched genome-wide in gene regulatory sequences, specifically enhancers, active during human embryonic craniofacial development. We demonstrated here that these enhancers also show enrichment of dental phenotype-associated variants, which is conserved in embryonic mouse craniofacial enhancers. Given these findings in bulk craniofacial tissues, we looked to determine the role of tooth enhancers in this phenomenon. We performed ChIP-seq and functionally annotated the genome of E13.5 mouse incisors, identifying enhancers. Multi-tissue comparisons of human and mouse enhancers revealed that putative tooth enhancers had the strongest enrichment of variants associated with dental phenotypes. These findings suggested a role for dysregulation of tooth development in dental phenotypes and diseases. To uncover novel dental phenotype-driving genes in the developing tooth we performed coexpression analysis on E12.5-E17.5 mouse incisors and molars, and annotated the contributing cell types of gene modules using scRNAseq of E14 molars. Through integration of chromatin state, bulk gene coexpression, and cell type resolved gene expression we prioritized a list of candidate novel dental disease genes for future investigations in mouse models and human studies.

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Mouse Dspp frameshift model of human dentinogenesis imperfecta

Cited by 13 publications

References 50 publications

Dentin defects caused by a Dspp−1 frameshift mutation are associated with the activation of autophagy

Dentin defects caused by a Dspp−1 frameshift mutation are associated with the activation of autophagy

Integration of multimodal data in the developing tooth reveals candidate regulatory loci driving human odontogenic phenotypes

“Integration of multimodal data in the developing tooth reveals candidate dental disease genes”

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