BMP gradients: A paradigm for morphogen-mediated developmental patterning

Bier, Ethan; Robertis, Edward M. De

doi:10.1126/science.aaa5838

Cited by 265 publications

(256 citation statements)

References 115 publications

(102 reference statements)

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“…The etiology of these deficits remains enigmatic to date. Precise regulation of BMP, Wnt, and Ras/ERK signaling is crucial to normal brain development (39)(40)(41)(42), raising the possibility that genotype might influence neurocognitive outcome, as appears to be the case for congenital heart disease (22,23). The results provide a means of stratifying non-syndromic patients to assess the extent to which specific genotypes contribute to neurocognitive outcome.…”

Section: Discussionmentioning

confidence: 99%

De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis

Timberlake

Furey

Choi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

100

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Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 × 10 −11 ). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity.

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Section: Discussionmentioning

confidence: 99%

De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis

Timberlake

Furey

Choi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

100

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“…The Chordin/BMP pathway is ancestral and conserved in bilateral animals as diverse as Drosophila, spiders, amphioxus, hemichordates, sea urchins, and vertebrates (Bier & De Robertis, 2015). We proposed that the remarkable conservation of the Hox genes (Carrasco, McGinnis, Gehring, & De Robertis, 1984) and of the BMP/Dpp, and Chordin/Sog systems between Drosophila and Xenopus suggested that these patterning systems were present in Urbilateria, the common ancestor of all bilateral animals .…”

Section: The Ancestral Chordin/bmp Morphogenetic Pathwaymentioning

confidence: 99%

“…We collaborated with F. Michael Hoffman and Edwin "Chip" Ferguson, who had independently cloned sog, to show that microinjected chordin and sog mRNA induced neural tissue both in Drosophila and frog embryos (Holley et al, 1995). This led to the realization that we had discovered an ancient D-V patterning molecule that had been conserved during evolution between fruit fly and amphibian embryos (reviewed in Bier & De Robertis, 2015;De Robertis, 2008). Importantly, the phenotypic effects of sog mutations were known to be enhanced when the dosage of dpp/BMP4 genes was increased in Drosophila (Ferguson & Anderson, 1992).…”

Section: The Cloning Of Chordinmentioning

confidence: 99%

The Chordin Morphogenetic Pathway

Robertis

Moriyama

2016

Current Topics in Developmental Biology

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“…Morphogens are diffusible factors that influence developmental patterns by forming gradients, which specify different fates for cells (Bier and De Robertis 2015). Thus, BMPs exert their actions in a dose‐dependent fashion.…”

Section: Introductionmentioning

confidence: 99%

BMP7 dose-dependently stimulates proliferation and cadherin-11 expression via ERK and p38 in a murine metanephric mesenchymal cell line

2017

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BMP7 is expressed in ureteric buds and cap mesenchyme of the fetal kidney, mediating branching morphogenesis and survival and priming of metanephric mesenchyme. Although dose‐dependent effects of BMP7 in collecting duct cells have been reported, studies in metanephric mesenchymal cells are lacking. We examined the effects of BMP7 on MAP kinase activation, proliferation, and expression of cadherins in a metanephric mesenchymal cell line MS7 by thymidine incorporation, immunoblot analysis, and quantitative real‐time PCR. The levels of phosphorylated ERK (P‐ERK) and phosphorylated p38 (P‐p38) were not altered at 10 min, 1 h, and 6 h with low‐dose BMP7 (0.25 nmol/L), but were increased at 24 h. At 24 h, P‐ERK was increased with low‐dose BMP7, but not by intermediate‐ (1 nmol/L) or high‐dose (10 nmol/L) BMP7, whereas p38 was activated by intermediate‐dose BMP7. Cell proliferation of MS7 was significantly increased by low‐ and intermediate‐dose BMP7 and decreased by high‐dose BMP7. A p38 inhibitor SB203580 5 μmol/L or a MEK inhibitor PD98059 5 μmol/L abolished BMP7‐stimulated proliferation. Expression of cadherin‐11, an adhesion molecule known to promote cell migration and compaction, was upregulated by intermediate‐dose BMP7. BMP7‐induced cadherin‐11 expression was inhibited by cotreatment with SB203580 and PD98059. Finally, in metanephroi cultured with siRNA for cadherin‐11, the number and thickness of cap mesenchyme were reduced. In conclusion, BMP7 exerts differential effects depending on the concentration; it may expand mesenchymal cells in the stroma where BMP7 concentration is low and may upregulate cadherin‐11 promoting condensation around the tip of ureteric buds.

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BMP gradients: A paradigm for morphogen-mediated developmental patterning

Cited by 265 publications

References 115 publications

De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis

De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis

The Chordin Morphogenetic Pathway

BMP7 dose-dependently stimulates proliferation and cadherin-11 expression via ERK and p38 in a murine metanephric mesenchymal cell line

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