Multiple Signals Converge on a Differentiation MAPK Pathway

An important emerging question in the area of signal transduction is how information from different pathways becomes integrated into a highly coordinated response. In budding yeast, multiple pathways regulate filamentous growth, a complex differentiation response that occurs under specific environmental conditions. To identify new aspects of filamentous growth regulation, we used a novel screening approach (called secretion profiling) that measures release of the extracellular domain of Msb2p, the signaling mucin which functions at the head of the filamentous growth (FG) MAPK pathway. Secretion profiling of complementary genomic collections showed that many of the pathways that regulate filamentous growth (RAS, RIM101, OPI1, and RTG) were also required for FG pathway activation. This regulation sensitized the FG pathway to multiple stimuli and synchronized it to the global signaling network. Several of the regulators were required for MSB2 expression, which identifies the MSB2 promoter as a target “hub” where multiple signals converge. Accessibility to the MSB2 promoter was further regulated by the histone deacetylase (HDAC) Rpd3p(L), which positively regulated FG pathway activity and filamentous growth. Our findings provide the first glimpse of a global regulatory hierarchy among the pathways that control filamentous growth. Systems-level integration of signaling circuitry is likely to coordinate other regulatory networks that control complex behaviors

Aiming for study comparability in Parkinson's disease: Proposal for a modular set of biomarker assessments to be used in longitudinal studies.

Parkinson's disease (PD) is an example for a complex field of research, which is driven by the multifactorial etiology, the heterogeneity in phenotype and the variability in disease progression, as well as the presence of a long pre-diagnostic period, called prodromal PD, lasting up to decades (Postuma et al., 2010). The very slow, so far inevitably progressive, neurodegenerative process and the multidimensional heterogeneity of symptoms in kind (motor and non-motor), time of onset and speed of progression call for prediction markers and progression markers to understand the onset of neurodegeneration and its course. These markers would also help to establish endpoints for neuroprotective treatment strategies aiming to modify disease progression. Because of the complexity, heterogeneity, and the progressive nature of PD, such predictive and progression markers can only be identified in large cohorts and in studies with a longitudinal design. A considerable number of longitudinal cohort studies in PD patients, as well as in individuals at risk, are currently being performed, and extensive effort has gone into the characterization of the individuals assessed. Although each study has its own value and merits, many important research questions cannot be answered as the numbers of participants are too small (e.g., when studying conversion to PD in at-risk populations). Moreover, the pivotal combination of data and findings across studies is hampered by the lack of comparability of symptoms/factors that are being assessed and the specific assessments that are being applied. Therefore, a common approach is needed to enable harmonization and combination of data across studies to define and validate predictive and progression markers. Based on the need for harmonized assessments of symptoms/markers in PD, the working group: Harmonization of biomarker assessment in longitudinal cohort studies in Parkinson's Disease (BioLoC-PD) of the Joint Programme for Neurodegenerative Diseases (JPND), set out to develop an assessment battery that includes the most useful clinical, laboratory, and brain imaging assessments for (longitudinal) studies in PD. We here describe the result of the process to find a way to harmonize assessments across studies and propose a modular set of biomarker assessments agreed upon by the group of experts who were included in the working group (all authors of this manuscript).</p