Distinct transcriptomic profiles guide early development of maxillary and mandibular teeth

The interaction between genetics and tissue environment shapes how individual teeth form in different regions of the jaw. While most experimental studies have focused on mandibular (lower jaw) teeth, little was known about how human maxillary (upper jaw) and mandibular teeth diverge at the molecular level during early development.

In a new study published in Oral Science and Homeostatic Medicine, a collaborative team from Beijing Stomatological Hospital, Capital Medical University, and Peking University School and Hospital of Stomatology performed a RNA-sequencing analysis of human fetal tooth germs at the cap stage (11–12 post-conception weeks). They compared gene expression profiles between pooled maxillary and mandibular tooth germs and validated key findings with quantitative PCR and immunofluorescence staining.

Upper and lower tooth germs show distinct transcriptomic profiles at the cap stage

Morphologically, both upper and lower tooth germs displayed typical cap-stage features, but principal component analysis of the RNA-seq data revealed a clear separation between maxillary and mandibular samples, indicating distinct transcriptional signatures despite their similar morphology.

The team identified 14,267 genes that were highly expressed in both regions, enriched in pathways related to extracellular matrix organization, TGF-β, WNT, NOTCH and BMP signaling, reflecting a shared core program for epithelial–mesenchymal interactions and early odontogenesis.

Upper tooth germs are enriched for morphogenesis-related genes, whereas lower tooth germs are enriched for mineralization-related genes.

Beyond this common framework, 687 genes were differentially expressed between the two regions: 282 were upregulated in maxillary tooth germs and 405 in mandibular tooth germs.

Maxillary-enriched genes, including GATA3, SHOX2 and PAX3, were associated with embryonic organ morphogenesis, regulation of FGF and BMP signaling, and extracellular matrix remodeling. These genes have been previously implicated in craniofacial patterning, palatal development and upper jaw formation.

In contrast, mandibular-enriched genes such as HAND2, DLX6, NKX2-3, PHEX and DMP1 were linked to actin-based movement, calcium ion transport and homeostasis, dentinogenesis and cytokine secretion-processes that support mineralized tissue formation and mechanical function.

"Even though the tooth germs in the upper and lower jaws look very similar at the cap stage, their gene expression patterns are diverging," said Ran Zhang, corresponding author of the study.

Protein–protein interaction network analysis highlighted several hub regulators, including IHH, HAND2, PAX3 and SP7, that connect multiple signaling pathways and may orchestrate region-specific tooth germ differentiation.

Validation at RNA and protein levels

To confirm the RNA-seq results, the investigators selected 18 representative genes for RT-qPCR. Most showed significant and consistent regional differences, with SHOX2, CHRDL1, GATA3, SP7 and PAX3 higher in maxillary tooth germs, and DMP1, NKX2-3, PHEX, HAND2 and DLX6 higher in mandibular tooth germs.

Immunofluorescence staining additionally showed that DLX6 and PHEX were strongly expressed in mandibular tooth germs, whereas SHOX2 was predominantly expressed in the maxillary tooth germs, revealing both regional and compartment-specific expression across epithelium and mesenchyme.

"These region-specific regulatory programs likely contribute to the distinct eruption timing, crown morphology and functional specialization of maxillary and mandibular teeth," said corresponding author Songlin Wang.

Implications and next steps

Human embryonic samples at this stage are extremely rare, so the authors acknowledge the modest sample size as a limitation but emphasize the value of obtaining direct human data rather than extrapolating solely from animal models. They suggest that functional studies in model organisms, guided by the identified hub genes and pathways, will be needed to decode how these transcriptional programs translate into jaw-specific tooth morphology.

The RNA-seq data from this study have been deposited in the CNGB Sequence Archive (accession CNP0008028) to facilitate reuse by the dental research community.