Sonic hedgehog is not a limb morphogen but acts as a trigger to specify all digits in mice

Zhu, Jianjian; Patel, Rashmi; Trofka, Anna; Harfe, Brian D.; Mackem, Susan

doi:10.1016/j.devcel.2022.07.016

Cited by 28 publications

(34 citation statements)

References 65 publications

(129 reference statements)

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“…In contrast, loss of Smarcc1 was unable to rescue the Shh phenotype: DKO forelimbs and hindlimbs were indistinguishable from Shh -/- (n=4 of each genotype; Figure 4C-J). A limitation to interpreting these results is that GLI3 repression and HH signaling have essential early roles in limb specification and thus it is possible that Smarcc1 conditional deletion occurs too late to rescue the phenotype (Lex et al, 2022; Scherz et al, 2007; Zhu et al, 2008; Zhu et al, 2022). However, the conditional deletion of Shh results in a hypomorphic phenotype with reduced numbers of digits, suggesting that inhibition of GLI repression should have resulted in some improvement of the phenotype.…”

Section: Resultsmentioning

confidence: 99%

The BAF chromatin complex component SMARCC1 does not mediate GLI transcriptional repression of Hedgehog target genes in limb buds

Ramachandran

Chen

Lex

et al. 2023

Preprint

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The Hedgehog (HH) signaling pathway is primarily modulated by GLI transcriptional repression in the mouse limb. Previous studies have suggested a role for the BAF chromatin remodeling complex in mediating GLI repression. Consistent with this possibility, the core BAF complex protein SMARCC1 is present at most active limb enhancers including the majority of GLI enhancers. Despite this, we find that SMARCC1 maintains chromatin accessibility at GLI enhancers suggesting that it contributes to enhancer activation rather than helping to mediate GLI repression. Furthermore, SMARCC1 binds GLI-regulated enhancers independently of GLI3 and does not facilitate transcriptional repression of most GLI target genes. Finally, Smarcc1- and Shh- double knockout phenotypes suggest that SMARCC1 is not required to mediate constitutive GLI repression in HH mutants. We conclude that the BAF complex does not mediate GLI3 repression, which we propose instead utilizes alternative chromatin remodeling complexes.

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Section: Resultsmentioning

confidence: 99%

The BAF chromatin complex component SMARCC1 does not mediate GLI transcriptional repression of Hedgehog target genes in limb buds

Ramachandran

Chen

Lex

et al. 2023

Preprint

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“…If the latter model is correct, the developmental rescue by an all-or-none OptoSOS input may not be an example of a simple input replacing the function of a complex one, but rather a good approximation of endogenous activation in the terminal system. A number of systems once thought to depend strictly on input concentration have similarly been shown to depend on an unexpectedly simple form of the input (Zhu et al 2022; Economou et al 2022).…”

Section: Discussionmentioning

confidence: 99%

Dynamics of an incoherent feedforward loop drive ERK-dependent pattern formation in the earlyDrosophilaembryo

Oatman

McFann

et al. 2023

Preprint

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Positional information in developing tissues often takes the form of stripes of gene expression that mark the boundaries of a particular cell type or morphogenetic process. How stripes form is still in many cases poorly understood. Here we use optogenetics and live-cell biosensors to investigate one such pattern: the posterior stripe ofbrachyenteron (byn)expression in the earlyDrosophilaembryo. Thisbynstripe depends on interpretation of an upstream signal — a gradient of ERK kinase activity — and the expression of two target genestailless (tll)andhuckebein (hkb)that exert antagonistic control overbyn. We find that high or low doses of ERK signaling produce either transient or sustainedbynexpression, respectively. These ERK stimuli also regulatetllandhkbexpression with distinct dynamics:tlltranscription is rapidly induced under both low and high stimuli, whereashkbtranscription converts graded ERK inputs into an output switch with a variable time delay. Antagonistic regulatory paths acting on different timescales are hallmarks of an incoherent feedforward loop architecture, which is sufficient to explain transient or sustainedbyndynamics and adds temporal complexity to the steady-state model ofbynstripe formation. We further show that an all-or-none stimulus can be blurred through intracellular diffusion to non-locally produce a stripe ofbyngene expression. Overall, our study provides a blueprint for using optogenetic inputs to dissect developmental signal interpretation in space and time.

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“…[80] Sonic hedgehog (Shh) is thought to be a morphogen controlling limb patterning and growth, but by bypassing its cell survival role during limb outgrowth, it was shown that Shh does not act as a long-range morphogen but rather as a short-range trigger to specify all the digits. [81] Manipulating morphogen spreading also revealed previously unappreciated roles of morphogen dispersal. By applying HA trap to study Gbb (Glass bottom boat), another BMP type ligand, it has recently been shown that the active BMP-type ligands in the wing imaginal disc are heterodimers of Dpp and Gbb [82] as previously shown in the case of the formation of the posterior crossvein in the pupal wing.…”

Section: Biological and Experimental Relevance For Other Morphogen Sy...mentioning

confidence: 97%

Is Drosophila Dpp/BMP morphogen spreading required for wing patterning and growth?

Matsuda

Affolter

2023

BioEssays

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Secreted signaling molecules act as morphogens to control patterning and growth in many developing tissues. Since locally produced morphogens spread to form a concentration gradient in the surrounding tissue, spreading is generally thought to be the key step in the non‐autonomous actions. Here, we review recent advances in tool development to investigate morphogen function using the role of decapentaplegic (Dpp)/bone morphogenetic protein (BMP)‐type ligand in the Drosophila wing disc as an example. By applying protein binder tools to distinguish between the roles of Dpp spreading and local Dpp signaling, we found that Dpp signaling in the source cells is important for wing patterning and growth but Dpp spreading from this source cells is not as strictly required as previously thought. Given recent studies showing unexpected requirements of long‐range action of different morphogens, manipulating endogenous morphogen gradients by synthetic protein binder tools could shed more light on how morphogens act in developing tissues.

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Sonic hedgehog is not a limb morphogen but acts as a trigger to specify all digits in mice

Cited by 28 publications

References 65 publications

The BAF chromatin complex component SMARCC1 does not mediate GLI transcriptional repression of Hedgehog target genes in limb buds

The BAF chromatin complex component SMARCC1 does not mediate GLI transcriptional repression of Hedgehog target genes in limb buds

Dynamics of an incoherent feedforward loop drive ERK-dependent pattern formation in the earlyDrosophilaembryo

Is Drosophila Dpp/BMP morphogen spreading required for wing patterning and growth?

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