title: Diffusible signals and epigenetic timing cooperate in late proximo-distal limb patterning.
abstract: Developing vertebrate limbs initiate proximo-distal patterning by interpreting opposing gradients of diffusible signaling molecules. We report two thresholds of proximo-distal signals in the limb bud: a higher threshold that establishes the upper-arm to forearm transition; and a lower one that positions a later transition from forearm to hand. For this last transition to happen, however, the signal environment seems to be insufficient, and we show that a timing mechanism dependent on histone acetylation status is also necessary. Therefore, as a consequence of the time dependence, the lower signaling threshold remains cryptic until the timing mechanism reveals it. We propose that this timing mechanism prevents the distal transition from happening too early, so that the prospective forearm has enough time to expand and form a properly sized segment. Importantly, the gene expression changes provoked by the first transition further regulate proximo-distal signal distribution, thereby coordinating the positioning of the two thresholds, which ensures robustness. This model is compatible with the most recent genetic analyses and underscores the importance of growth during the time-dependent patterning phase, providing a new mechanistic framework for understanding congenital limb defects.
authors.affiliation: Departamento de Desarrollo y Reparación Cardiovascular, Centro Nacional de Investigaciones Cardiovasculares, CNIC, c/ Melchor Fernández Almagro, 3, 28029 Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Roselló-Díez
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Arques
authors.forename: Irene
authors.initials: I
authors.lastname: Delgado
authors.forename: Giovanna
authors.initials: G
authors.lastname: Giovinazzo
authors.forename: Miguel
authors.initials: M
authors.lastname: Torres
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics*; D002642:Chick Embryo; D004058:Diffusion; D004622:Embryo, Mammalian; D044127:Epigenesis, Genetic / Q000502:physiology*; D005121:Extremities / Q000196:embryology*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors
chemical_list: D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; C099959:homeobox protein HOXA13
keywords: Chick; Epigenetics; FGF; Hox; Meis; Mouse; Patterning; Proximo-distal; Retinoic acid; Vertebrate limb