Developmental stalling and organ-autonomous regulation of morphogenesis

Abstract

Timing of organ development during embryogenesis is coordinated such that at birth, organ and fetal size and maturity are appropriately proportioned. The extent to which local developmental timers are integrated with each other and with the signaling interactions that regulate morphogenesis to achieve this end is not understood. Using the absolute requirement for a signaling pathway activity (bone morphogenetic protein, BMP) during a critical stage of tooth development, we show that suboptimal levels of BMP signaling do not lead to abnormal morphogenesis, as suggested by mutants affecting BMP signaling, but to a 24-h stalling of the intrinsic developmental clock of the tooth. During this time, BMP levels accumulate to reach critical levels whereupon tooth development restarts, accelerates to catch up with development of the rest of the embryo and completes normal morphogenesis. This suggests that individual organs can autonomously control their developmental timing to adjust their stage of development to that of other organs. We also find that although BMP signaling is critical for the bud-to-cap transition in all teeth, levels of BMP signaling are regulated differently in multicusped teeth. We identify an interaction between two homeodomain transcription factors, Barx1 and Msx1, which is responsible for setting critical levels of BMP activity in multicusped teeth and provides evidence that correlates the levels of Barx1 transcriptional activity with cuspal complexity. This study highlights the importance of absolute levels of signaling activity for development and illustrates remarkable self-regulation in organogenesis that ensures coordination of developmental processes such that timing is subordinate to developmental structure.

Localised inhibition of FGF signalling in the third pharyngeal pouch is required for normal thymus and parathyroid organogenesis

“…These observations suggest that an early defect in Foxn1 expression can recover to allow for normal development to ensue. A similar example of a recovery of an early defect in tooth development due to deficient BMP signalling was recently reported, suggesting that this phenomenon of 'developmental stalling' might be a common feature of BMPregulated developmental processes (Miletich et al, 2011).…”

Roles of Bmp4 during tooth morphogenesis and sequential tooth formation

“…Moreover, tissue-specific inactivation of Bmpr1a in epithelial tissues resulted in tooth developmental arrest at the bud stage (Andl et al, 2004;Liu et al, 2005). These data led to the conclusion that Bmp4 is a key Msx1-dependent signal for induction of PEK formation to drive tooth morphogenesis beyond the bud stage (Bei et al, 2000;Miletich et al, 2011;O'Connell et al, 2012;Zhao et al, 2000). However, direct genetic analysis of the requirement for Bmp4 in early tooth morphogenesis has not been documented.…”

“…−/− mutant embryos was suggested to be caused by a reduction of mesenchymal Bmp4 mRNA expression in the tooth mesenchyme at E13.5 as detected by in situ hybridization (Miletich et al, 2011 tooth germ explants supplemented with exogenous Bmp4 progressed to the stage of dentin formation whereas the Bmp4 transgene driven by the Msx1 promoter only rescued a low percentage of Msx1 −/− mutant molar tooth germs to early cap stage without further morphogenesis (Bei et al, 2000;Zhao et al, 2000). Thus, although our findings indicate that endogenous mesenchymal Bmp4 plays crucial roles in tooth development, this study reveals an important gap in the understanding of Msx1-mediated regulation of mesenchymal odontogenic activity.…”

barx1represses joints and promotes cartilage in the craniofacial skeleton

“…barx1 is required for tooth and musculoskeletal attachment barx1 is required for proper oral tooth development in mice (Miletich et al, 2011), and barx1 is expressed in the pharyngeal dentition in cichlids and zebrafish (Fraser et al, 2009;Sperber and Dawid, 2008). Zebrafish pharyngeal tooth development progresses through initiation, morphogenesis, matrix deposition and attachment (Van der Heyden and Huysseune, 2000).…”