# Functional causality in regulating cell morphogenesis

> **NIH NIH R35** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $858,982

## Abstract

Morphogenesis is a fundamental process in a wide range of cell functions and therefore one of the best
studied. Consequently, most of the contributing component processes and the majority of their molecular parts
are known. Much less understood is how the many underlying component processes are integrated into a
working whole. This integration is regulated by a system of chemical and mechanical pathways with i) a high
level of non-linearity; ii) a high level of redundancy; and iii) a separation in space and time of cause and effect
between component processes. A key consequence of such a pathway configuration is that perturbation of any
component can lead to wide-ranging and fast adaptation. Hence, phenotypic changes primarily reflect a
reconfiguration of the system and not necessarily the function of the perturbed target. This challenge has
plagued the interrogation of molecular functions in cell morphogenesis, and has led to numerous controversies
that likely relate to slight differences in experimental designs triggering divergent adaptation processes. To
circumvent some of these limitations, my lab has developed over the past 10 years quantitative live cell
imaging methods that reveal the functional interplay between spatially and temporally distributed molecular
processes, such as cytoskeleton polymer dynamics, forces, and chemical signals, based on the coupling of
their spontaneous activation fluctuations in unperturbed systems. Building on key discoveries of cell
morphogenic control mechanisms, which required the use of a perturbation-free approach rather than a more
conventional experimental paradigm, we propose here an extension of this research program that will
introduce a rigorous statistical framework to infer the coupling of molecular processes in cause and effect
cascades. This includes algorithms to identify directly, from fluctuation time series, feedback interactions
between processes and the dynamic rewiring of the cause and effect cascades under variable cellular
conditions. These computational developments will be paralleled by innovation in experimental systems for
multispectral live cell imaging of up to 8 concurrent processes and for the analysis of cell morphogenesis in
native tissue environments in 3D. The studies will be focused on the coordination of the system of highly
redundant actin modulating factors in promoting actin mediated cell shape changes and the interactions of this
system with the regulatory system of RhoGTPase signals. The impact of this work will reach far beyond the
new insights we will gain of the regulation of these pathway systems. The work will address the notorious
adaptation responses of complex molecular systems, which are generic and a fundamental impediment to the
systematic inquiry of cell functions. The tools we develop to overcome some of these problems will be made
available as widely-adoptable approaches to the analysis of cell regulatory processes.

## Key facts

- **NIH application ID:** 10401805
- **Project number:** 5R35GM136428-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Gaudenz Danuser
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $858,982
- **Award type:** 5
- **Project period:** 2020-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401805

## Citation

> US National Institutes of Health, RePORTER application 10401805, Functional causality in regulating cell morphogenesis (5R35GM136428-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10401805. Licensed CC0.

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