Hedgehog-FGF Signaling Axis Patterns Anterior Mesoderm During Gastrulation

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2020 Jun 21

PMID 32561646

Citations 22

Authors

Alexander Guzzetta

Mervenaz Koska

Megan Rowton

Kaelan R Sullivan

Jessica Jacobs-Li

Junghun Kweon

Hunter Hidalgo

Heather Eckart

Andrew D Hoffmann

Rebecca Back

Stephanie Lozano

Anne M Moon

Anindita Basu

Michael Bressan

Sebastian Pott

Ivan P Moskowitz

Affiliations

Soon will be listed here.

Abstract

The mechanisms used by embryos to pattern tissues across their axes has fascinated developmental biologists since the founding of embryology. Here, using single-cell technology, we interrogate complex patterning defects and define a Hedgehog (Hh)-fibroblast growth factor (FGF) signaling axis required for anterior mesoderm lineage development during gastrulation. Single-cell transcriptome analysis of Hh-deficient mesoderm revealed selective deficits in anterior mesoderm populations, culminating in defects to anterior embryonic structures, including the pharyngeal arches, heart, and anterior somites. Transcriptional profiling of Hh-deficient mesoderm during gastrulation revealed disruptions to both transcriptional patterning of the mesoderm and FGF signaling for mesoderm migration. Mesoderm-specific / double-mutants recapitulated anterior mesoderm defects and Hh-dependent GLI transcription factors modulated enhancers at FGF gene loci. Cellular migration defects during gastrulation induced by Hh pathway antagonism were mitigated by the addition of FGF4 protein. These findings implicate a multicomponent signaling hierarchy activated by Hh ligands from the embryonic node and executed by FGF signals in nascent mesoderm to control anterior mesoderm patterning.

Citing Articles

Sonic Hedgehog signaling regulates the optimal differentiation pace from early-stage mesoderm to cardiogenic mesoderm in mice.

Inoue S, Nosetani M, Nakajima Y, Sakaki S, Kato H, Saba R Dev Growth Differ. 2025; 67(2):75-84.

PMID: 39783159 PMC: 11842887. DOI: 10.1111/dgd.12955.

The molecular mechanisms of cardiac development and related diseases.

Li Y, Du J, Deng S, Liu B, Jing X, Yan Y Signal Transduct Target Ther. 2024; 9(1):368.

PMID: 39715759 PMC: 11666744. DOI: 10.1038/s41392-024-02069-8.

An explainable map of human gastruloid morphospace reveals gastrulation failure modes and predicts teratogens.

Rufo J, Qiu C, Han D, Baxter N, Daley G, Wilson M bioRxiv. 2024; .

PMID: 39386623 PMC: 11463602. DOI: 10.1101/2024.09.20.614192.

Signaling Pathways Governing Cardiomyocyte Differentiation.

Mensah I, Gowher H Genes (Basel). 2024; 15(6).

PMID: 38927734 PMC: 11202427. DOI: 10.3390/genes15060798.

P4HA2 hydroxylates SUFU to regulate the paracrine Hedgehog signaling and promote B-cell lymphoma progression.

Li Q, Liu Y, Wu J, Zhu Z, Fan J, Zhai L Leukemia. 2024; 38(8):1751-1763.

PMID: 38909089 PMC: 11286522. DOI: 10.1038/s41375-024-02313-8.

References

Vokes S, Yatskievych T, Heimark R, McMahon J, McMahon A, Antin P . Hedgehog signaling is essential for endothelial tube formation during vasculogenesis. Development. 2004; 131(17):4371-80. DOI: 10.1242/dev.01304. View

Stuart T, Butler A, Hoffman P, Hafemeister C, Papalexi E, Mauck 3rd W . Comprehensive Integration of Single-Cell Data. Cell. 2019; 177(7):1888-1902.e21. PMC: 6687398. DOI: 10.1016/j.cell.2019.05.031. View

Weinstein D, Ruiz i Altaba A, Chen W, Hoodless P, Prezioso V, Jessell T . The winged-helix transcription factor HNF-3 beta is required for notochord development in the mouse embryo. Cell. 1994; 78(4):575-88. DOI: 10.1016/0092-8674(94)90523-1. View

Francou A, Saint-Michel E, Mesbah K, Theveniau-Ruissy M, Rana M, Christoffels V . Second heart field cardiac progenitor cells in the early mouse embryo. Biochim Biophys Acta. 2012; 1833(4):795-8. DOI: 10.1016/j.bbamcr.2012.10.003. View

Tam P, Behringer R . Mouse gastrulation: the formation of a mammalian body plan. Mech Dev. 1998; 68(1-2):3-25. DOI: 10.1016/s0925-4773(97)00123-8. View

Burgess R, Rawls A, Brown D, Bradley A, Olson E . Requirement of the paraxis gene for somite formation and musculoskeletal patterning. Nature. 1996; 384(6609):570-3. DOI: 10.1038/384570a0. View

Hoffmann A, Yang X, Burnicka-Turek O, Bosman J, Ren X, Steimle J . Foxf genes integrate tbx5 and hedgehog pathways in the second heart field for cardiac septation. PLoS Genet. 2014; 10(10):e1004604. PMC: 4214600. DOI: 10.1371/journal.pgen.1004604. View

Ramilowski J, Goldberg T, Harshbarger J, Kloppmann E, Kloppman E, Lizio M . A draft network of ligand-receptor-mediated multicellular signalling in human. Nat Commun. 2015; 6:7866. PMC: 4525178. DOI: 10.1038/ncomms8866. View

St-Jacques B, Dassule H, Karavanova I, Botchkarev V, Li J, Danielian P . Sonic hedgehog signaling is essential for hair development. Curr Biol. 1998; 8(19):1058-68. DOI: 10.1016/s0960-9822(98)70443-9. View

10.

Sun X, Meyers E, Lewandoski M, Martin G . Targeted disruption of Fgf8 causes failure of cell migration in the gastrulating mouse embryo. Genes Dev. 1999; 13(14):1834-46. PMC: 316887. DOI: 10.1101/gad.13.14.1834. View

11.

Kinder S, Tsang T, Wakamiya M, Sasaki H, Behringer R, Nagy A . The organizer of the mouse gastrula is composed of a dynamic population of progenitor cells for the axial mesoderm. Development. 2001; 128(18):3623-34. DOI: 10.1242/dev.128.18.3623. View

12.

Daane J, Downs K . Hedgehog signaling in the posterior region of the mouse gastrula suggests manifold roles in the fetal-umbilical connection and posterior morphogenesis. Dev Dyn. 2011; 240(9):2175-93. PMC: 3265168. DOI: 10.1002/dvdy.22711. View

13.

Briscoe J, Therond P . The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol. 2013; 14(7):416-29. DOI: 10.1038/nrm3598. View

14.

Liao Y, Smyth G, Shi W . featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2013; 30(7):923-30. DOI: 10.1093/bioinformatics/btt656. View

15.

Chapman S, Collignon J, Schoenwolf G, Lumsden A . Improved method for chick whole-embryo culture using a filter paper carrier. Dev Dyn. 2001; 220(3):284-9. DOI: 10.1002/1097-0177(20010301)220:3<284::AID-DVDY1102>3.0.CO;2-5. View

16.

Macosko E, Basu A, Satija R, Nemesh J, Shekhar K, Goldman M . Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets. Cell. 2015; 161(5):1202-1214. PMC: 4481139. DOI: 10.1016/j.cell.2015.05.002. View

17.

Goodrich L, Milenkovic L, Higgins K, Scott M . Altered neural cell fates and medulloblastoma in mouse patched mutants. Science. 1997; 277(5329):1109-13. DOI: 10.1126/science.277.5329.1109. View

18.

Yoder M . Inducing definitive hematopoiesis in a dish. Nat Biotechnol. 2014; 32(6):539-41. DOI: 10.1038/nbt.2929. View

19.

Kelly R, Buckingham M, Moorman A . Heart fields and cardiac morphogenesis. Cold Spring Harb Perspect Med. 2014; 4(10). PMC: 4200205. DOI: 10.1101/cshperspect.a015750. View

20.

Madisen L, Zwingman T, Sunkin S, Oh S, Zariwala H, Gu H . A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci. 2009; 13(1):133-40. PMC: 2840225. DOI: 10.1038/nn.2467. View