bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.08.20.608898

Mll4 regulates tooth enamel development

Lee, J.-M.·Jung, H.·Tang, Q.·An, W.·Lee, S.-K.·Lee, J. W.·Kwon, H.-J.
View original source ↗Export metadata ↓

Abstract

Amelogenesis, the process of enamel formation, is tightly regulated and essential for producing the tooth enamel that protects teeth from decay and wear. Disruptions in amelogenesis can result in amelogenesis imperfecta, a group of genetic conditions characterized by defective enamel, including enamel hypoplasia, marked by thin or underdeveloped enamel. Mutations in the KMT2D (MLL4) gene, which encodes a histone H3-lysine 4-methyltransferase, are associated with Kabuki syndrome, a developmental disorder that can involve dental anomalies such as enamel hypoplasia. However, the specific role of KMT2D in amelogenesis remains poorly understood. To address this gap, we generated a conditional knockout mouse model with ectoderm-specific deletion of Kmt2d (Krt14-Cre;Kmt2dfl/fl, or Kmt2d-cKO) and characterized the resulting enamel defects using gross, radiographic, histological, cellular, and molecular analyses. Micro-computed tomography and scanning electron microscopy revealed that adult Kmt2d-cKO mice exhibited 100% penetrant amelogenesis imperfecta, characterized by hypoplastic and hypomineralized enamel, partially phenocopying human Kabuki syndrome. Additionally, Kmt2d-cKO neonates developed molar tooth germs with subtle cusp shape alterations and mild delays in ameloblast differentiation at birth. RNA-seq analysis of the first molar tooth germ at birth revealed that 33.7% of known amelogenesis-related genes were significantly downregulated in the Kmt2d-cKO teeth. Integration with KMT2D CUT&RUN-seq results identified 8 overlapping genes directly targeted by KMT2D. Re-analysis of a single-cell RNA-seq dataset in the developing mouse incisors revealed distinct roles for these genes in KMT2D-regulated differentiation across various cell subtypes within the dental epithelium. Among these genes, Satb1 and Sp6 are likely direct targets involved in the differentiation of pre-ameloblasts into ameloblasts. Taken together, we propose that KMT2D plays a crucial role in amelogenesis by directly activating key genes involved in ameloblast differentiation, offering insights into the molecular basis of enamel development and related dental pathologies.

Source connections

Explore related subjects

developmental biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Lee, J.-M., Jung, H., Tang, Q., An, W., Lee, S.-K., Lee, J. W., Kwon, H.-J.. 2024-08-21. Mll4 regulates tooth enamel development. https://doi.org/10.1101/2024.08.20.608898

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Proteome-wide quantification of protein turnover in frog and fly embryos reveals divergent strategies of maternal inheritance

Every embryo inherits a maternal proteome that it must remodel with zygotic proteins to build its many cell types. The fate of the maternal proteome remains contested because indirect measurements cannot resolve it. Here, we combine 18O-water labeling with multiplexed proteomics to quantify protein turnover proteome-wide in frog and fly embryos. Through hatching, the frog preserves the bulk of its maternal proteome, confining rapid degradation to a small regulatory module. The fly cannot meet its synthesis demand from yolk alone and instead degrades nearly all maternal proteins, including housekeeping proteins long assumed stable, recycling them into new protein. Yet the turnover hierarchy is conserved, with disordered and regulatory proteins degrading fastest, while the fly rescales the whole proteome ~eightfold faster. These results recast the developmental proteome as both informational inheritance and metabolic reserve, establish 18O-water labeling as a turnover method for non-feeding organisms, and provide a resource of embryonic half-lives.

developmental biology↗
bioRxiv2026

The MAPK phosphatase VHP-1 buffers pharynx-to-body proportions against tissue-specific growth imbalance in C. elegans

Maintaining appropriate organ size ratios in the face of growth fluctuations is critical for the development of a reproducible body plan. Yet the mechanisms involved remain poorly understood. Here, we investigated how pharynx-to-body proportions are maintained in Caenorhabditis elegans, combining tissue-specific perturbations, genetic screening, and longitudinal live imaging. A genome-wide RNAi screen revealed that knock-down of the dual-specificity MAPK phosphatase VHP-1 turns animals hypersensitive to inter-tissue growth imbalance caused by pharyngeal or epidermal depletion of the mTORC1 activator RAGA-1 or the ribosomal protein RPL-22. In contrast, vhp-1 mutants tolerated global raga-1 loss, indicating a specific requirement for vhp-1 under tissue growth imbalance. Knock-down of the p38 pathway suppressed the imbalance-specific defects of vhp-1 mutants. In contrast, JNK knock-down effectively rescued the pleiotropic phenotypes of vhp-1 mutants but only weakly reduced their sensitivity to RAGA-1 imbalance, indicating that these two stress-MAPK pathways make distinct contributions to the response to growth imbalance. Finally, whole-animal VHP-1 levels increased upon epidermal RAGA-1 depletion, and epidermal VHP-1 depletion did not reproduce the sensitivity caused by global vhp-1 loss, consistent with a contribution from VHP-1 outside the growth-perturbed epidermis in buffering against local growth imbalance.

developmental biology↗
bioRxiv2026

Network topology reveals distinct forms of developmental leverage in the Drosophila wing

Developmental gene regulatory networks reliably transform positional information into complex multicellular form, yet the organizational principles linking network architecture to developmental mechanism remain poorly understood. Here, we analyzed the Drosophila melanogaster wing developmental network to determine whether network topology reflects the distribution of developmental leverage during organogenesis. Integration of curated wing-development genes with high-confidence STRING interactions revealed five Hierarchical Layers of Developmental Control (HLDCs) associated with distinct topological and developmental roles. Organizer Centers, Signaling Scaffolds, and Pattern Implementers formed a forward-specification axis in which connectivity progressively contracted as positional information was transformed into increasingly localized developmental programs. Interface Coordinators departed from this hierarchy through disproportionate brokerage, whereas Local Modulators retained connectivity despite localized developmental scope. We propose that these complementary signatures reflect two regulatory architectures: 1) hierarchical information propagation that generates developmental identity and 2) distributed homeostatic regulation that coordinates and refines developmental outputs. Within Character Identity Modules (ChiMOs), this architecture links conserved patterning systems, Hox-defined contexts, and organ-specific kernels to reproducible morphology, providing a mechanistic hypothesis for developmental canalization and experimentally testable predictions.

developmental biology↗