Secreted, receptor-associated bone morphogenetic protein regulators reduce stochastic noise intrinsic to many extracellular morphogen distributions

Abstract

Morphogens are secreted molecules that specify cell-fate organization in developing tissues. Patterns of gene expression or signalling immediately downstream of many morphogens such as the bone morphogenetic protein (BMP) decapentaplegic (Dpp) are highly reproducible and robust to perturbations. This contrasts starkly with our expectation of a noisy interpretation that would arise out of the experimentally determined low concentration (approximately picomolar) range of Dpp activity, tight receptor binding and very slow kinetic rates. To investigate mechanisms by which the intrinsic noise can be attenuated in Dpp signalling, we focus on a class of secreted proteins that bind to Dpp in the extracellular environment and play an active role in regulating Dpp/receptor interactions. We developed a stochastic model of Dpp signalling in Drosophila melanogaster and used the model to quantify the extent that stochastic fluctuations would lead to errors in spatial patterning and extended the model to investigate how a surface-associated BMP-binding protein (SBP) such as Crossveinless-2 (Cv-2) may buffer out signalling noise. In the presence of SBPs, fluctuations in the level of ligand-bound receptor can be reduced by more than twofold depending on parameter values for the intermediate transition states. Regulation of receptor -ligand interactions by SBPs may also increase the frequency of stochastic fluctuations providing a separation of timescales between high-frequency receptor equilibration and slower morphogen patterning. High-frequency noise generated by SBP regulation is easily attenuated by the intracellular network creating a system that imitates the performance of a simple low-pass filter common in audio and communication applications. Together, these data indicate that one of the benefits of receptor-ligand regulation by secreted non-receptors may be greater reliability of morphogen patterning mechanisms.

Efficient calculation of steady state probability distribution for stochastic biochemical reaction network

“…This result supports a previous assumption made in [4] where the recruitment of Type II receptor was excluded to simplify the modeling steps while characterizing the noise profile of a SBP regulated BMP signaling system.…”

“…The parameter screen on the intermediate dynamics yields three primary qualitative subclasses for Cv-2 behavior in regulation of extracellular BR (C) fluctuation amplitude: i) reduced amplitude ii) increased amplitude and iii) mixed amplitude behavior [4]. Three primary types of responses of Cv-2 action on BMP fluctuations are shown in Figure 2a-c.…”

Semi-adaptive response and noise attenuation in bone morphogenetic protein signalling

“…Mathematical models concerning BMP signalling mainly focused on receptor dynamics [30] or steady-state behaviour of mutual-inhibition loops [23]. However, temporal dynamics of the BMP signalling network including intracellular molecules and its role in noise attenuation have not been studied.…”

The Role of Mathematical Models in Understanding Pattern Formation in Developmental Biology

“…In other work on the same network, Karim et al modeled the local receptor/ligand/ Cv-2 interactions and found that Cv-2 imparts signaling robustness to small levels of BMP ligand and overcomes the slow receptor dynamics, which leads to a high fidelity interpretation of the extracellular gradient over time (Karim et al 2012). In this model, Cv-2 significantly reduces signaling noise, leading to a more reliable interpretation of position and a sharper, more reliable boundary.…”