Hedgehog signaling activates a mammalian heterochronic gene regulatory network controlling differentiation timing across lineages

Rowton, Megan; Perez-Cervantes, Carlos; Hur, Suzy S J; Jacobs-Li, Jessica; Lu, Emery; Deng, Nikita; Guzzetta, Alexander; Hoffmann, Andrew D.; Stocker, Matthew; Steimle, Jeffrey D.; Lazarevic, Sonja; Oubaha, Sophie; Yang, Xinan; Kim, Chul; Yu, Shu-Han; Eckart, Heather; Koska, Mervenaz; Hanson, Erika; Chan, Sunny Sun Kin; Garry, Daniel J.; Kyba, Michael; Basu, Anindita; Ikegami, Kohta; Pott, Sebastian; Moskowitz, Ivan P.

doi:10.1016/j.devcel.2022.08.009

Cited by 5 publications

(7 citation statements)

References 190 publications

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“…Previous work established that in zebrafish Hh signaling is required during early patterning stages to promote the proper number of differentiated ACs and VCs [55], while a requirement at later stages of somitogenesis and posterior SHF addition equivalent to those examined in this study was not found. Consistent with the previous observations of the temporal requirements of Hh signaling [55,83], we did not find it was required upstream of Wnt signaling or Foxf. Instead, we found that there was a minimal effect of Hh signaling repressing the 3’reg1:GFP reporter, which was the opposite of what would be expected from the mammalian data.…”

Section: Discussionsupporting

confidence: 92%

“…Consistent with the previous observations of the temporal requirements of Hh signaling [55,83], we did not find it was required upstream of Wnt signaling or Foxf. Instead, we found that there was a minimal effect of Hh signaling repressing the 3'reg1:GFP reporter, which was the opposite of what would be expected from the mammalian data.…”

Section: Discussionsupporting

confidence: 91%

“…It is interesting to consider the lack of conservation of these upstream factors in the regulation of the vertebrate posterior SHF. The posterior SHF-derived cells that contribute to the single atrium and venous pole in zebrafish are significantly less than that found in mice [70,83]. By virtue of its lack of requirement, our work would support the proposed hypothesis whereby heterochrony of a Hh-dependent regulatory network may have contributed to the enlargement of the posterior SHF and the concurrent the evolution of the pulmonary system in air-breathing vertebrates [69,83].…”

Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 66%

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A Foxf1-Wnt-Nr2f1 cascade promotes atrial cardiomyocyte differentiation in zebrafish

Coppola,

Kenney,

Waxman

2024

Preprint

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Nr2f transcription factors (TFs) are conserved regulators of vertebrate atrial cardiomyocyte (AC) differentiation. However, little is known about the mechanisms directing Nr2f expression in ACs. Here, we identified a conserved enhancer 3′ to the nr2f1a locus, which we call 3’reg1-nr2f1a (3′reg1), that can promote Nr2f1a expression in ACs. Sequence analysis of the enhancer identified putative Lef/Tcf and Foxf TF binding sites. Mutation of the Lef/Tcf sites within the 3′reg1 reporter, knockdown of Tcf7l1a, and manipulation of canonical Wnt signaling support that Tcf7l1a is derepressed via Wnt signaling to activate the transgenic enhancer and promote AC differentiation. Similarly, mutation of the Foxf binding sites in the 3′reg1 reporter, coupled with gain- and loss-of-function analysis supported that Foxf1 promotes expression of the enhancer and AC differentiation. Functionally, we find that Wnt signaling acts downstream of Foxf1 to promote expression of the 3′reg1 reporter within ACs and, importantly, both Foxf1 and Wnt signaling require Nr2f1a to promote a surplus of differentiated ACs. CRISPR-mediated deletion of the endogenous 3’reg1 abrogates the ability of Foxf1 and Wnt signaling to produce surplus ACs in zebrafish embryos. Together, our data support that downstream members of a conserved regulatory network involving Wnt signaling and Foxf1 function on a nr2f1a enhancer to promote AC differentiation in the zebrafish heart.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 66%

See 2 more Smart Citations

A Foxf1-Wnt-Nr2f1 cascade promotes atrial cardiomyocyte differentiation in zebrafish

Coppola,

Kenney,

Waxman

2024

Preprint

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“…We describe SHH having an inhibitory effect on tracheal chondrogenesis. While this is consistent with the way the loss of Hh activity permits differentiation during morphogenesis of other organs (Hebrok et al 1998; Fagman et al 2004; Grevellec et al 2011; Rowton et al 2022), it stands in contrast to genetic data showing that SHH activity is required for airway cartilage formation in the mouse (Miller et al 2004; Park et al 2010; Sala et al 2011). This seeming contradiction might be explained by a critical difference in the architecture of the tracheal cartilage elements in birds vs. mammals.…”

Section: Resultssupporting

confidence: 83%

A dynamic Hedgehog gradient orients tracheal cartilage rings

Kingsley,

Mishkind,

Hiscock

et al. 2023

Preprint

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SUMMARYThe patterning of periodic stripes during embryonic development generates similar structures that repeat at regular spatial intervals within a tissue. These patterns are often attributed to a Turing-like mechanism, which self-organizes characteristically spaced stripes, but these patterns are predicted to be disorganized. Conversely, well-oriented, parallel stripes are often observed in nature. We investigate this phenomenon during the formation of the cartilage rings that support the amniote airway. We find evidence that a Turing-like mechanism underpins the formation of the repeating cartilage elements. Additionally,SHHis transiently expressed in a thin dorsal domain along the length of the developing trachea, resulting in a dorsoventral gradient of Hedgehog activity that recedes over time. Using mathematical modelling, we predict that the spatiotemporal dynamics of the gradient are required to organize the stripes into parallel rings. Comparingin silicopredictions with experimental SHH manipulations shows that the Hedgehog gradient is essential for proper tracheal cartilage patterning.

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Rare homozygous cilia gene variants identified in consanguineous congenital heart disease patients

Baird,

Mubeen,

Doganli

et al. 2023

Preprint

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BACKGROUND: Congenital heart defects (CHD) appear in almost one percent of live births. Asian countries have the highest birth prevalence of CHD in the world. Recessive genotypes may represent a significant CHD risk factor in Asian populations, because Asian populations have a high degree of consanguineous marriages, which increases the risk of CHD. Genetic analysis of consanguineous families may represent a relatively unexplored source for investigating CHD etiology. METHODS: To obtain insight into the contribution of recessive genotypes in CHD we analysed a cohort of forty-nine Pakistani CHD probands, originating from consanguineous unions. The majority (82%) of patients malformations were septal defects. We identified protein altering, rare homozygous variants (RHVs) in the patients coding genome by whole exome sequencing. RESULTS: The patients had a median of seven damaging RHVs each, and our analysis revealed a total of 758 RHVs in 693 different genes. By prioritizing these genes based on variant severity, loss-of-function intolerance and specific expression in the developing heart, we identified a set of 23 candidate disease genes. These candidate genes were significantly enriched for genes known to cause heart defects in recessive mouse models (P<2.4e-06). In addition, we found a significant enrichment of cilia genes in both the initial set of 693 genes (P<5.4e-04) and the 23 candidate disease genes (P<5.2e-04). Functional investigation of ADCY6 in cell- and zebrafish-models verified its role in heart development. CONCLUSIONS: Our results confirm a significant role for cilia genes in recessive forms of CHD and suggest important functions of cilia genes in cardiac septation.

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Hedgehog signaling activates a mammalian heterochronic gene regulatory network controlling differentiation timing across lineages

Cited by 5 publications

References 190 publications

A Foxf1-Wnt-Nr2f1 cascade promotes atrial cardiomyocyte differentiation in zebrafish

A Foxf1-Wnt-Nr2f1 cascade promotes atrial cardiomyocyte differentiation in zebrafish

A dynamic Hedgehog gradient orients tracheal cartilage rings

Rare homozygous cilia gene variants identified in consanguineous congenital heart disease patients

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