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An oscillatory transcription factor complex regulates adaptive changes in macropinocytosis during the growth-to-development transition

ABSTRACT: Macropinocytosis is an evolutionarily conserved endocytic pathway that mediates non-selective bulk uptake of extracellular fluid. It is the major route by which axenic Dictyostelium cells obtain nutrients and has emerged as a nutrient-scavenging pathway for mammalian cells. How cells adjust macropinocytic activity in various physiological or developmental contexts is an important question that remains largely unanswered. We discovered that, in Dictyostelium cells, the transcription factors Hbx5 and MybG form a functional complex in the nucleus to maintain macropinocytic activity during the growth stage. In contrast, during starvation-induced multicellular development, the transcription factor complex undergoes nucleocytoplasmic shuttling in response to oscillatory cyclic adenosine 3',5'-monophosphate (cAMP) signals, which leads to increased cytoplasmic retention of the complex and progressive downregulation of macropinocytosis. Therefore, by coupling macropinocytosis-related gene expression to the cAMP oscillation system that facilitates long-range cell-cell communication, the dynamic translocation of the Hbx5-MybG complex orchestrates a population-level adjustment of macropinocytic activity to adapt to changing environmental conditions.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Dictyostelium Discoideum (slime Mold)

TISSUE(S): Cell Culture

SUBMITTER: Yazhou Hao

LAB HEAD: Huaqing Cai

PROVIDER: PXD046585 | Pride | 2024-01-12

REPOSITORIES: Pride

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Project description:Oscillatory phenomena are ubiquitous across different biological scales, from individual cells to tissues and whole organisms. In physical systems, oscillatory behaviour can emerge from weak coupling of independent stochastic elements. Once established, oscillations can drive coordinated group behaviour and encode robust information through oscillation frequency or amplitude. Here we use experimentation and modelling to understand the emergence and information coding properties of oscillatory cyclic adenosine monophosphate (cAMP) signaling in D. discoideum. Oscillatory cAMP signaling drives aggregation of individual amoebae and coordinated temporal shifts in gene expression. However, it is unknown how the collective behaviour emerges and attenuates in an auto-regulatory manner where temporal transcriptional regulation must decode variation in cAMP pulse count, frequency, or amplitude. To address these questions, we identified a transcription factor, Hbx5, that is essential for the initiation of collective behaviour and its activity provides a single-cell readout of the earliest sign of cAMP signaling. This reveals stochastic pulses in cAMP signaling precede collective oscillations, with Hbx5 dependent transcriptional feedback enhancing signal sensitivity necessary for the emergence of collective oscillations. We demonstrate that once collective oscillations have been established, another cAMP-regulated transcription factor, GtaC, required for subsequent developmental progression becomes activated. Modelling and experimentation suggest that temporal differences in transcription factor activation arise from differences in the threshold at which the protein kinase, ErkB, influences their activity. This leads us to propose that changes in the amplitude of cAMP oscillations during development encode temporal information, driving the orderly progression of development. These studies thus provide crucial insights into the principles driving collective behaviour and the evolution of multicellular systems.

			Action	DRS
	20191227GFP1.msf	Msf
	20191227GFP1.raw	Raw
	20191227GFP2.raw	Raw
	20191227GFP3.raw	Raw
	20191227GFP4.raw	Raw

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An oscillatory transcription factor complex regulates adaptive changes in macropinocytosis during the growth-to-development transition

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