Dataset Information

Disrupted early molar patterning in syngnathia mouse model

ABSTRACT: It is well established that tooth morphogenesis initiates at embryonic day 10.5 (E10.5), characterized by the specification of a single molar germ in each jaw quadrant. However, the developmental mechanisms underlying the establishment of spatially distinct maxillary and mandibular identities along the jaw axis prior to this stage remain elusive. In Wnt1-Cre;pMes-Bmp4 transgenic mice, a pathological model recapitulating human syngnathia (resulting in bilateral jaw fusion), we demonstrate here that BMP4 overexpression in cranial neural crest cells (CNCCs) disrupts early molar patterning with 100% penetrance, manifesting as the formation of only one molar germ within the unilateral fused jaw structure, establishing this model as a valuable tool for investigating the patterning of maxillary and mandibular molar germs during jaw development. Systematic analysis of wild-type embryos revealed the emergence of a single molar primordium in the unilateral first pharyngeal arch (PA1) by E9.0. This primordium undergoes segregation to form the maxillary and mandibular molar between E9.5-E9.75, a process synchronized with the anteroposterior patterning of PA1. Comparative studies with the mutant model indicated that this developmental segregation depends on coordinated migration of CNCC-derived molar primordium and a BMP4/FGF8-dependent gene regulatory network (GRN) at the maxillomandibular junction. Pathologically elevated BMP4 signaling upregulates the p38 intracellular pathway in the mutant jaws, perturbing the finely tuned GRN and disrupting post-migratory CNCC migration. These perturbations collectively lead to defective molar segregation in syngnathia mouse model. Our findings elucidate fundamental mechanisms governing early molar patterning and may provide molecular explanations for syngnathia-associated molar oligodontia in humans.

ORGANISM(S): Mus musculus

PROVIDER: GSE309624 | GEO | 2025/10/14

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Previous studies have suggested that Bmp4 is a key Msx1-dependent mesenchymal odontogenic signal for driving tooth morphogenesis through the bud-to-cap transition. Whereas the bud stage tooth developmental arrest in Msx1-/- mutant mice was accompanied by reduction in mesenchymal Bmp4 mRNA expression, we show that depleting functional Bmp4 mRNAs in the tooth mesenchyme, through neural crest-specific gene inactivation in Bmp4f/f;Wnt1Cre mice, caused mandibular molar developmental arrest at the bud stage but allowed maxillary molars and incisors to develop to mineralized teeth. We show that the Wnt inhibitors Dkk2 and Wif1 were much more abundantly expressed in the mandibular than maxillary molar mesenchyme in wildtype embryos and that Dkk2 expression was significantly unregulated in the tooth mesenchyme in Bmp4f/f;Wnt1Cre embryos. In addition, expression of Osr2, which encodes a zinc finger protein that antagonizes Msx1-mediated activation of odontogenic mesenchyme, is significantly upregulated in the molar mesenchyme in Bmp4f/f;Wnt1Cre embryos. Msx1 heterozygosity enhanced maxillary molar developmental defects whereas Osr2 heterozygosity rescued mandibular first molar morphogenesis in Bmp4f/f;Wnt1Cre mice. Moreover, in contrast to complete lack of supernumerary tooth initiation in Msx1-/-Osr2-/- mutant mice, Osr2-/-Bmp4f/f;Wnt1Cre compound mutant mice exhibit formation and subsequent arrest of supernumerary tooth germs that correlated with down regulation of Msx1 expression in the tooth mesenchyme. Taken together, our data indicate that, while reduction in mesenchymal Bmp4 expression alone could not account for the tooth bud arrest phenotype in Msx1-/- mutant mice, Bmp4 signaling synergizes with Msx1 and antagonizes Osr2 to activate mesenchymal odontogenic activity to drive tooth morphogenesis and sequential tooth formation. E13.5 mouse embryos tooth germs were microdissected by laser capture microdissection (LCM), and the mandibular molar and maxillary molar were separated. 3 pairs of control and mutant samples were pooled for the RNA extraction.

Project description:Growth and patterning of the face relies on several small buds of tissue, the facial prominences, which surround the primitive mouth. Beginning around E10 of mouse development the prominences undergo rapid growth and morphogenesis. By E11.5 the medial nasal prominences are in close apposition in the midline, as are the maxillary and medial nasal prominences on either side of the developing face. Subsequently, by E12.5 the nasal and maxillary prominences fuse to form a continuous shelf at the front of the face - the primary palate. Individual prominences are associated with specific developmental processes, and this is reflected by patterns of differential gene expression that give the prominences their unique identities. Thus, only the mandibular and maxillary prominences give rise to dentition while the frontonasal prominence has a unique role in olfaction, and the mandibular prominence in taste. We used microarrays to detail the differential gene expression program in each of the mandibular, maxillary, and frontonasal prominences during the key developmental timepoints of E10.0 through E12.5. Experiment Overall Design: Analysis of gene expression during growth and fusion of the facial prominences in the C57BL/6J mouse strain between embryonic (E) day 10.0 and 12.5. At the earliest timepoint, E10, only the mandibular prominence is a distinct entity that can be readily identified and dissected. The frontonasal prominence and the maxillary prominence are very small and not discrete from other components of the head such as the forebrain until E10.5. Analysis of these tissues at earlier timepoints would require laser capture and preamplification steps - techniques that were not used for the later timepoints. Thus samples were isolated from the mandibular prominence at E10.0 and from the mandibular, maxillary and frontonasal prominences of mouse embryos from E10.5 to E12.5, at 0.5 day intervals. In order to obtain sufficient sample for hybridization, each sample represents a pool of between 3 and 48 embryos depending on the timepoint. Specifically, the number of embryos were 40-48 for E10.0 (mandibular prominence only), 24-8 for E10.5, 8-9 for E11.0 and E11.5 and 3-4 for E12.0 and E12.5. Seven replicate samples were taken for each of the later five timepoints in each of the three prominences, with an additional seven samples for the mandibular E10.0 timepoint, for a total of 112 samples.

Dataset Information

Disrupted early molar patterning in syngnathia mouse model

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets