Optogenetic investigation of BMP target gene expression diversity

Rogers, Katherine W.; ElGamacy, Mohammad; Jordan, Benjamin M; Müller, Patrick

doi:10.7554/elife.58641

Cited by 40 publications

(57 citation statements)

References 112 publications

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“…When adding the inhibitor at 24h, TFAP2C expands inward and goes up in the colony center but is not uniform and a small number SOX17+TFAP2C+ PGCLCs is present. Our observation of inward expansion of TFAP2C is consistent with findings in zebrafish, where TFAP2C was found to be a direct target of BMP whose expression is excluded from the margin by FGF/ERK signaling (Rogers et al 2020), suggesting conserved regulation by signaling of this gene despite diverging functions.…”

Section: Nodal and Fgf Signaling Are Required On The Second Day Of Pgclc Specificationsupporting

confidence: 90%

Efficient differentiation of human primordial germ cells through geometric control reveals a key role for NODAL signaling

Teague

Chen

et al. 2021

Preprint

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Human primordial germ cells (hPGCs) form around the time of implantation and are the precursors of eggs and sperm. Many aspects of hPGC specification remain poorly understood. Here we show that micropatterned human pluripotent stem cells (hPSCs) treated with BMP4 give rise to hPGC-like cells (hPGCLC) and use these as a quantitatively reproducible and simple in vitro model to interrogate this important developmental event. We characterize micropatterned hPSCs up to 96h for the first time and show that hPGCLC populations are stable and continue to mature. By perturbing signaling during hPGCLC differentiation, we identify a previously unappreciated role for NODAL signaling and find that the relative timing and duration of BMP and NODAL signaling are critical parameters controlling the number of hPGCLCs. We formulate a mathematical model for a network of cross-repressive fates driven by NODAL and BMP signaling which predicts the measured fate patterns after signaling perturbations. Finally, we show that hPSC colony size dictates the efficiency of hPGCLC specification, which led us to dramatically improve the efficiency of hPGCLC differentiation over current protocols.

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Section: Nodal and Fgf Signaling Are Required On The Second Day Of Pgclc Specificationsupporting

confidence: 90%

Efficient differentiation of human primordial germ cells through geometric control reveals a key role for NODAL signaling

Teague

Chen

et al. 2021

Preprint

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“…Having generated a specific smad4a mutant we next investigated how loss of Smad4a influenced Nodal- and BMP-induced transcription. We initially explored BMP and Nodal transcriptional outputs at mid gastrulation, a time at which these ligands pattern the embryo through well-described arrays of target genes 49 , 50 . We performed RNA-seq on WT and MZ smad4a embryos at 50% epiboly and compared three biological replicates for each condition (Fig.…”

Section: Resultsmentioning

confidence: 99%

Smad4 controls signaling robustness and morphogenesis by differentially contributing to the Nodal and BMP pathways

et al. 2021

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The transcriptional effector SMAD4 is a core component of the TGF-β family signaling pathways. However, its role in vertebrate embryo development remains unresolved. To address this, we deleted Smad4 in zebrafish and investigated the consequences of this on signaling by the TGF-β family morphogens, BMPs and Nodal. We demonstrate that in the absence of Smad4, dorsal/ventral embryo patterning is disrupted due to the loss of BMP signaling. However, unexpectedly, Nodal signaling is maintained, but lacks robustness. This Smad4-independent Nodal signaling is sufficient for mesoderm specification, but not for optimal endoderm specification. Furthermore, using Optical Projection Tomography in combination with 3D embryo morphometry, we have generated a BMP morphospace and demonstrate that Smad4 mutants are morphologically indistinguishable from embryos in which BMP signaling has been genetically/pharmacologically perturbed. Smad4 is thus differentially required for signaling by different TGF-β family ligands, which has implications for diseases where Smad4 is mutated or deleted.

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“…Fur-thermore, it is known that multiple morphogen profiles relay combinatorial input signals that determine the expressions of an array of downstream target genes and their subsequent interactions [66][67][68] . Ongoing studies employing model systems including the fruit fly, zebrafish, chicken, and mouse are providing key insights into complex tissue patterning mechanisms 9,10, [69][70][71][72][73] .…”

Section: Discussionmentioning

confidence: 99%

Cost-precision trade-off relation determines the optimal morphogen gradient for accurate biological pattern formation

Song

Hyeon

2021

Preprint

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Spatial boundaries growing into macroscopic structures through animal development originate from the pre-patterning of tissues by signaling molecules, called morphogens. To establish accurate boundaries, the morphogen concentration which thresholds the expression of target gene at the boundary should be precise enough, exhibiting large gradient and small fluctuations. Producing more morphogens would better serve to shape more precise target boundaries; however, it incurs more thermodynamic cost. In the classical diffusion-degradation model of morphogen profile formation, the morphogens synthesized from a local source display an exponentially decaying concentration profile with a characteristic length λ. Our theory suggests that in order to attain a precise morphogen profile with the minimal cost, λ should be roughly half the distance to the target boundary position from the source, so that the boundary is formed at the position where the morphogen concentration is ~10% of the value at the source. Remarkably, we find that the well characterized morphogens that pattern the fruit fly embryo and wing imaginal disk form profiles with nearly optimal λ, which underscores the thermodynamic cost as a key physical constraint in the morphogen profile formation.

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Optogenetic investigation of BMP target gene expression diversity

Cited by 40 publications

References 112 publications

Efficient differentiation of human primordial germ cells through geometric control reveals a key role for NODAL signaling

Efficient differentiation of human primordial germ cells through geometric control reveals a key role for NODAL signaling

Smad4 controls signaling robustness and morphogenesis by differentially contributing to the Nodal and BMP pathways

Cost-precision trade-off relation determines the optimal morphogen gradient for accurate biological pattern formation

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