title: Semi-adaptive response and noise attenuation in bone morphogenetic protein signalling.
abstract: Temporal dynamics of morphogen-driven signalling events are critical for proper embryonic development. During development, cells translate extracellular bone morphogenetic protein (BMP) gradients, often subject to noise, into graded intracellular tail-phosphorylated SMAD (TP-SMAD) levels. Using modelling and experimental approaches, we found that BMPs induce TP-SMAD responses in neural precursor cells in a concentration-dependent manner, which are semi-adaptive within a specific intermediate range of BMP concentration. These semi-adaptive TP-SMAD responses involve an intrinsically slow deactivation of BMP receptors, which attenuates noise by prolonging SMAD deactivation time after BMP withdrawal, but increases response time. Interestingly, negative feedback on BMP receptors is also required for semi-adaptation, which benefits both noise attenuation and response time, and therefore balances the trade-off seen with slow BMP receptor deactivation. These results highlight the rich dynamics of SMAD regulation in response to graded BMP concentration, and elucidate general design principles for balancing noise attenuation and activation speed in signalling systems.
authors.affiliation: Department of Mathematics, University of California, Irvine, CA, USA Center for Complex Biological Systems, University of California, Irvine, CA, USA.
authors.forename: Tian
authors.initials: T
authors.lastname: Hong
authors.affiliation: Center for Complex Biological Systems, University of California, Irvine, CA, USA Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA.
authors.forename: Ernest S
authors.initials: ES
authors.lastname: Fung
authors.affiliation: Beijing International Center for Mathematical Research, Peking University, Beijing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Huynh
authors.affiliation: Center for Complex Biological Systems, University of California, Irvine, CA, USA Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA emonuki@uci.edu.
authors.forename: Edwin S
authors.identifier: http://orcid.org/0000-0001-5130-781X
authors.initials: ES
authors.lastname: Monuki
authors.affiliation: Department of Mathematics, University of California, Irvine, CA, USA Center for Complex Biological Systems, University of California, Irvine, CA, USA qnie@uci.edu.
authors.forename: Qing
authors.initials: Q
authors.lastname: Nie
mesh_terms: D000818:Animals; D052004:Bone Morphogenetic Protein Receptors / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000196:embryology*; D047108:Embryonic Development / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D059629:Signal-To-Noise Ratio; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D051785:Smad Proteins; D052004:Bone Morphogenetic Protein Receptors
keywords: SMAD phosphorylation; activation time; adaptive response; negative feedback; noise attenuation; response speed