Biology subjects

Martinez-Mekler, G.

Publications and source records attributed to Martinez-Mekler, G..

4 recordsLinked to original sources

bioRxiv2021

Information Flow in the Fibroblast Growth Factor Receptor Communication Channel

In this work we analyze the flow of information through the Fibroblast Growth Factor Receptor (FGFR) communication channel when different types of signals are transmitted by the MAPK cascade to the gene regulatory network (GRN) formed by the genes C-Myc, DUSP, and Cdc25A, which control fibroblast proliferation. We used the canonical mathematical model of the MAPK cascade coupled to a stochastic model for the activation of the gene regulatory network, subject to different types of FGF inputs (step, quadratic pulses, Dirac delta, and white noise), in order to analyze the response of the gene regulatory network to each type of signal, and determine the temporal variation of the value of its Shannon entropy in each case. Our model suggests that the sustained activation of the FGFR communication channel with a step of FGF > 1 nM is required for cell cycle progression and that during the G1/S transition the amount of uncertainty of the GRN remains at a steady value of [~] 2.75 bits, indicating that while the fibroblast stimulation with FGF continues the G1/S transition does not require an additional interchange of information between the emitter and the gene regulatory network to be completed. We also found that either low frequency pulses of FGF or low frequency noise, both with a frequency f [≤] 2.77 Hz, are not filtered by the MAPK cascade and can modify the output of the communication channel, i.e., the amount of the effector proteins c-myc, cdc25A and DUSP. An additional effect suggested by our model is that o low frequency periodic signals and noise possibly blockage cell cycle progression because the threshold value concentration of cdc25A for the G1/S transition is not sustained in the in the nucleus during the 10 hours that this process lasts. Finally, from our model we can estimate the capacity of this communication channel in 0.96 bits/min.

biophysics↗

bioRxiv2021

Discrete dynamic model of the mammalian sperm acrosome reaction: the influence of acrosomal pH and biochemical heterogeneity

The acrosome reaction (AR) is an exocytotic process essential for mammalian fertilization. It involves diverse biochemical and physiological changes that culminate in the release of the acrosomal content to the extracellular medium as well as a reorganization of the plasma membrane (PM) that allows sperm to interact and fuse with the egg. In spite of many efforts, there are still important pending questions regarding the molecular mechanism regulating the AR. Particularly, the contribution of acrosomal alkalinization to AR triggering in physiological conditions is not well understood. Also, the dependence of the proportion of sperm capable of undergoing AR on the biochemical heterogeneity within a sperm population has not been studied. Here we present a discrete mathematical model for the human sperm AR, based on the biophysical and biochemical interactions among some of the main components of this complex exocytotic process. We show that this model can qualitatively reproduce diverse experimental results, and that it can be used to analyze how acrosomal pH (pHa) and cell heterogeneity regulate AR. Our results confirm that pHa increase can on its own trigger AR in a subpopulation of sperm, and furthermore, it indicates that this is a necessary step to trigger acrosomal exocytosis through progesterone, a known physiological inducer of AR. Most importantly, we show that the proportion of sperm undergoing AR is directly related to the detailed structure of the population biochemical heterogeneity.

systems biology↗

bioRxiv2021

Mathematical model reveals that heterogeneity in the number of ion transporters regulates the fraction of mouse sperm capacitation

Capacitation is a complex maturation process mammalian sperm must undergo in the female genital tract to be able to fertilize an egg. This process involves, amongst others, physiological changes in flagellar beating pattern, membrane potential, intracellular ion concentrations and protein phosphorylation. Typically, in a capacitation medium, only a fraction of sperm achieve this state. The cause for this heterogeneous response is still not well understood and remains an open question. Here, one of our principal results is to develop a discrete regulatory network, with mostly deterministic dynamics in conjunction with some stochastic elements, for the main biochemical and biophysical processes involved in the early events of capacitation. The model criterion for capacitation requires the convergence of specific levels of a select set of nodes. Besides reproducing several experimental results and providing some insight on the network interrelations, the main contribution of the model is the suggestion that the degree of variability in the total amount and individual number of ion transporters among spermatozoa regulates the fraction of capacitated spermatozoa. This conclusion is consistent with recently reported experimental results. Based on this mathematical analysis, experimental clues are proposed for the control of capacitation levels. Furthermore, cooperative and interference traits that become apparent in the modelling among some components also call for future theoretical and experimental studies. Author summaryFertilization is one of the fundamental processes for the preservation of life. In mammals, sperm undergo a complex process during their passage through the female tract known as capacitation, which enables them for fertilization. At the present time, it is accepted from experimental observation, though not understood, that only a fraction of the sperm is capacitated. In this work, by means of a network mathematical model for regulatory sperm intracellular signaling processes involved in mice capacitation, we find that the variability in the distribution of the number of ion transporters intervenes in the regulation of the capacitation fraction. Experimental verification of this suggestion could open a line of research geared to the regulation of the degree of heterogeneity in the number of ion transporters as a fertility control. The model also uncovers, through in silico overactivation and loss of function of network nodes, synergetic traits which again call for experimental verification.

developmental biology↗

bioRxiv2018

Interplay scenarios between CatSper and CaV channels in sea urchin sperm flagellum signaling cascades triggered by egg peptides: a mathematical modelling approach

Intracellular calcium ([Ca2+]i) is a basic, versatile and ubiquitous cellular signal controlling a wide variety of biological processes. A remarkable example is the steering of sea urchin spermatozoa towards the conspecific egg by a spatially and temporally orchestrated series of cytosolic [Ca2+]i spikes. Although this process has been an experimental paradigm for reproduction and sperm chemotaxis studies, the composition and regulation of the signalling network underlying the cytosolic calcium fluctuations are hitherto not fully understood. Here, we used a differential equations model of the signalling network to assess which set of channels can explain the characteristic envelop and temporal organisation of the [Ca2+]i-spike trains. The signalling network comprises an initial membrane hyperpolarisation/repolarisation produced by an upstream module triggered by the egg-released chemoattractant peptide, via receptor activation, cGMP synthesis and decay. Followed by downstream modules leading to pHi, voltage and [Ca2+]i fluctuations. The upstream module outputs were fitted to kinetic data on cGMP activity and early membrane potential changes measured in bulk cell populations. Two candidate modules featuring voltage-dependent Ca2+-channels link these outputs to the downstream dynamics and can independently explain the typical decaying envelop and the progressive spacing of the spikes. In the first module, [Ca2+]i-spike trains require the concerted action of a classical CaV-like channel and a potassium channel, BK (Slo1), whereas the second module relies on pHi-dependent, [Ca2+]i-inactivated CatSper dynamics alone. The model predicts that these two modules interfere with each other and produce unreasonable dynamics when present at similar proportions, which suggests that one may predominate over the other in vivo. To assess these alternatives, several quantitative predictions were derived from each module and confronted to experimental observations. We show that the [Ca2+]I dynamics observed experimentally after sustained alkalinisation can be reproduced by a model featuring the CatSper module but not by one including the pH-independent CaV and BK module. We conclude in favour of the module containing CatSper.

developmental biology↗