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Ascl5 variant alters gene expression in postnatal maxillary molars through potential gain-of-function effect

ABSTRACT: Lobodontia is a rare dental anomaly characterized by supernumerary cusps and a single, pyramid-shaped molar root resembling those of carnivorous mammals. Through genetic analysis of six unrelated families, we identified a novel heterozygous missense variant in the ASCL5 gene (c.274G>A; p.Glu92Lys) that segregates fully with the phenotype. To investigate the functional impact of this variant, we generated Ascl5 knock-in mutant mice using CRISPR/Cas9. Heterozygous (Ascl5Mut/WT) mice displayed dental anomalies consistent with human lobodontia, whereas homozygous (Ascl5Mut/Mut) mice exhibited more severe craniofacial abnormalities, highlighting the essential role of ASCL5 in tooth and jaw development. To explore the molecular basis of the dental phenotype, we performed transcriptomic analysis of maxillary first molars from postnatal day 1 (P1) Ascl5Mut/WT and Ascl5Mut/Mut mice, each compared to wild-type controls. Based on a gain-of-function hypothesis for the p.Glu89Lys variant, we focused on genes upregulated in both mutant genotypes. This analysis identified 87 commonly upregulated genes. Pathway enrichment analysis using Metascape revealed 11 significantly enriched biological pathways, including Dmp1, Phex, and Atg4b genes associated with biomineral tissue development. Notably, the regulatory region of Phex contains a conserved E-box motif, a known binding site for bHLH transcription factors such as ASCL5, suggesting it may be a direct transcriptional target.

ORGANISM(S): Mus musculus

PROVIDER: GSE296465 | GEO | 2025/12/07

REPOSITORIES: GEO

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Project description:Introduction: We have reported that iPSC-cardiac myocytes from patients with arrhythmogenic cardiomyopathy (ACM) mount an intense innate immune response under basal conditions in vitro. In addition, blocking innate immune signaling via NFκB prevents disease in a mouse model of ACM (Dsg2mut/mut mice). Here, we defined the relative pathogenic roles of immune signaling in cardiac myocytes vs. infiltrating inflammatory cells in Dsg2mut/mut mice. Methods: To define the role of immune signaling in cardiac myocytes, we bred Dsg2mut/mut mice with mice with cardiac myocyte-specific expression of a dominant-negative form of IκBα (DN-IκBα), which prevents nuclear translocation and, thereby, activation of NFκB signaling only in cardiac myocytes. To define the role of inflammatory cells in ACM, we focused on cells expressing C-C motif chemokine receptor-2 (CCR2+ cells), known to mediate adverse cardiac remodeling and fibrosis. We bred Dsg2mut/mut mice with germline deletion of Ccr2 mice (Ccr2-/- mice). We compared phenotypes in Dsg2mut/mut mice with double-mutant Dsg2mut/mut X DN-IκB and Dsg2mut/mut X Ccr2-/- lines. Results: Dsg2mut/mut mice develop marked myocardial fibrosis, reduced LV ejection fraction (EF) and many PVCs. These disease features were all normalized in Dsg2mut/mut X DN-IκB mice. Hearts of Dsg2mut/mut and Dsg2mut/mut X DN-IκB mice contained equal numbers of CD68+ macrophages, but Dsg2mut/mut hearts had many more CCR2+ cells. Cardiac myocyte expression of Tlr4 which activates NFκB, was increased in Dsg2mut/mut mice but not in Dsg2mut/mut X Ccr2-/- mice. Dsg2mut/mut X Ccr2-/- mice showed greatly reduced myocardial fibrosis and PVCs but LV EF was markedly depressed. This suggested that contractile dysfunction in ACM is due not only to loss of muscle but to immune signaling in viable cardiac myocytes as well. To test this hypothesis, we treated Dsg2mut/mut and Dsg2mut/mut X Ccr2-/- mice with the NFκB inhibitor Bay 11-7082. Before treatment, LV EFs were significantly reduced in both groups. Untreated Dsg2mut/mut mice had ongoing deterioration of LV function, whereas treated Dsg2mut/mut mice showed no further disease progression and actually had some improvement in contractile function. However, LV function in treated Dsg2mut/mut X Ccr2-/- mice was virtually normalized. Conclusions: NFκB signaling in cardiac myocytes drives myocardial injury, LV dysfunction and arrhythmias in Dsg2mut/mut mice. It also mobilizes CCR2+ cells to the heart, where they promote myocardial injury and arrhythmias. CCR2+ cells alter gene expression in cardiac myocytes. LV dysfunction in Dsg2mut/mut mice is caused not only by muscle loss but also by negative inotropic effects of inflammation mediated by NFκB in viable cardiac myocytes. These results have obvious implications for ACM patients and suggest that anti-inflammatory therapy may be beneficial even in patients with established disease.

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Ascl5 variant alters gene expression in postnatal maxillary molars through potential gain-of-function effect

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