Dataset Information

Decomposing a deterministic path to mesenchymal niche formation by two intersecting morphogen gradients.

ABSTRACT: Organ formation requires integrating signals to coordinate proliferation, specify cell fates, and shape tissue. Tracing these events and signals remains a challenge, as intermediate states across many critical transitions are unresolvable over real time and space. Here, we designed a unique computational approach to decompose a non-linear differentiation process into key components to resolve the signals and cell behaviors that drive a rapid transition, using the hair follicle dermal condensate as a model. Combining scRNA sequencing with genetic perturbation, we reveal that proliferative Dkk1+ progenitors transiently amplify to become quiescent dermal condensate cells by the mere spatiotemporal patterning of Wnt/β-catenin and SHH signaling gradients. Together, they deterministically coordinate a rapid transition from proliferation to quiescence, cell fate specification, and morphogenesis. Moreover, genetically repatterning these gradients reproduces these events autonomously in "slow motion" across more intermediates that resolve the process. This analysis unravels two morphogen gradients that intersect to coordinate events of organogenesis.

SUBMITTER: Qu R

PROVIDER: S-EPMC9050909 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Decomposing a deterministic path to mesenchymal niche formation by two intersecting morphogen gradients.

Qu Rihao R Gupta Khusali K Dong Danni D Jiang Yiqun Y Landa Boris B Saez Charles C Strickland Gwendolyn G Levinsohn Jonathan J Levinsohn Jonathan J Weng Pei-Lun PL Taketo M Mark MM Kluger Yuval Y Myung Peggy P

Developmental cell 20220413 8

Organ formation requires integrating signals to coordinate proliferation, specify cell fates, and shape tissue. Tracing these events and signals remains a challenge, as intermediate states across many critical transitions are unresolvable over real time and space. Here, we designed a unique computational approach to decompose a non-linear differentiation process into key components to resolve the signals and cell behaviors that drive a rapid transition, using the hair follicle dermal condensate ...[more]

PMID: 35421372

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Project description:Gene expression patterns in developing organisms are established by groups of cross-regulating target genes that are driven by morphogen gradients. As development progresses, morphogen activity is reduced, leaving the emergent pattern without stabilizing positional cues and at risk of rapid deterioration due to the inherently noisy biochemical processes at the cellular level. But remarkably, gene expression patterns remain spatially stable and reproducible over long developmental time spans in many biological systems. Here we combine spatial-stochastic simulations with an enhanced sampling method (Non-Stationary Forward Flux Sampling) and a recently developed stability theory to address how spatiotemporal integrity of a gene expression pattern is maintained in developing tissue lacking morphogen gradients. Using a minimal embryo model consisting of spatially coupled biochemical reactor volumes, we study a prototypical stripe pattern in which weak cross-repression between nearest neighbor expression domains alternates with strong repression between next-nearest neighbor domains, inspired by the gap gene system in the Drosophila embryo. We find that tuning of the weak repressive interactions to an optimal level can prolong stability of the expression patterns by orders of magnitude, enabling stable patterns over developmentally relevant times in the absence of morphogen gradients. The optimal parameter regime found in simulations of the embryo model closely agrees with the predictions of our coarse-grained stability theory. To elucidate the origin of stability, we analyze a reduced phase space defined by two measures of pattern asymmetry. We find that in the optimal regime, intact patterns are protected via restoring forces that counteract random perturbations and give rise to a metastable basin. Together, our results demonstrate that metastable attractors can emerge as a property of stochastic gene expression patterns even without system-wide positional cues, provided that the gene regulatory interactions shaping the pattern are optimally tuned.

Dataset Information

Decomposing a deterministic path to mesenchymal niche formation by two intersecting morphogen gradients.

Publications

Decomposing a deterministic path to mesenchymal niche formation by two intersecting morphogen gradients.

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