title: 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.
authors.affiliation: Department of Craniofacial Development, Dental Institute,  Kings College London, Guys Hospital, London SE1 6RT,  United Kingdom.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Miletich
authors.forename: Wei-Yuan
authors.initials: WY
authors.lastname: Yu
authors.forename: Ruofang
authors.initials: R
authors.lastname: Zhang
authors.forename: Kai
authors.initials: K
authors.lastname: Yang
authors.forename: Simone
authors.initials: S
authors.lastname: Caixeta de Andrade
authors.forename: Silvia Fontes do A
authors.initials: SF
authors.lastname: Pereira
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohazama
authors.forename: Orin B
authors.initials: OB
authors.lastname: Mock
authors.forename: Georg
authors.initials: G
authors.lastname: Buchner
authors.forename: Jane
authors.initials: J
authors.lastname: Sealby
authors.forename: Zoe
authors.initials: Z
authors.lastname: Webster
authors.forename: Minglian
authors.initials: M
authors.lastname: Zhao
authors.forename: Marianna
authors.initials: M
authors.lastname: Bei
authors.forename: Paul T
authors.initials: PT
authors.lastname: Sharpe
mesh_terms: D000367:Age Factors; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D005455:Fluorescent Antibody Technique; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D051957:MSX1 Transcription Factor / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009805:Odontogenesis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014070:Tooth / Q000196:embryology*; D014157:Transcription Factors / Q000378:metabolism*; D055114:X-Ray Microtomography
chemical_list: C490667:BARX1 protein, human; D019485:Bone Morphogenetic Proteins; D017931:DNA Primers; D018398:Homeodomain Proteins; D051957:MSX1 Transcription Factor; C484083:MSX1 protein, human; D014157:Transcription Factors
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