Smad1 and Smad5 differentially regulate embryonic hematopoiesis

Lisa J. McReynolds, Sunny Gupta, Maria Figueroa, Mary C. Mullins, Todd Evans

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

The bone morphogenetic protein (BMP) signaling pathway regulates multiple steps of hematopoiesis, mediated through receptor-regulated Smads, including Smad1 and Smad5. Here, we use loss-of-function approaches in zebrafish to compare the roles of Smad1 and Smad5 during embryonic hematopoiesis. We show that knockdown of Smad1 or Smad5 generates distinct and even opposite hematopoietic phenotypes. Embryos depleted for Smad1 have an increased number of primitive erythrocytes, but fail to produce mature embryonic macrophages. In contrast, Smad5-depleted embryos are defective in primitive erythropoiesis, yet have normal numbers of macrophages. Loss of either Smad1 or Smad5 causes a failure in the generation of definitive hematopoietic progenitors. To investigate the mechanism behind these phenotypes, we used rescue experiments and found that Smad5 is unable to rescue the Smad1 loss-of-function phenotype, indicating that the 2 highly related proteins have inherently distinct activities. Microarray experiments revealed that the 2 proteins redundantly regulate the key initiators of the hemato-vascular program, including scl, lmo2, and gfi1. However, each also regulates a remarkably distinct genetic program, with Smad5 uniquely regulating the BMP signaling pathway itself. Our results suggest that specificity of BMP signaling output, with respect to hematopoiesis, can be explained by differential functions of Smad1 and Smad5.

Original languageEnglish (US)
Pages (from-to)3881-3890
Number of pages10
JournalBlood
Volume110
Issue number12
DOIs
StatePublished - Dec 1 2007
Externally publishedYes

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Bone Morphogenetic Proteins
Hematopoiesis
Macrophages
Phenotype
Embryonic Structures
Erythrocyte Count
Erythropoiesis
Zebrafish
Microarrays
Blood Vessels
Proteins
Experiments

ASJC Scopus subject areas

  • Hematology

Cite this

McReynolds, L. J., Gupta, S., Figueroa, M., Mullins, M. C., & Evans, T. (2007). Smad1 and Smad5 differentially regulate embryonic hematopoiesis. Blood, 110(12), 3881-3890. https://doi.org/10.1182/blood-2007-04-085753

Smad1 and Smad5 differentially regulate embryonic hematopoiesis. / McReynolds, Lisa J.; Gupta, Sunny; Figueroa, Maria; Mullins, Mary C.; Evans, Todd.

In: Blood, Vol. 110, No. 12, 01.12.2007, p. 3881-3890.

Research output: Contribution to journalArticle

McReynolds, LJ, Gupta, S, Figueroa, M, Mullins, MC & Evans, T 2007, 'Smad1 and Smad5 differentially regulate embryonic hematopoiesis', Blood, vol. 110, no. 12, pp. 3881-3890. https://doi.org/10.1182/blood-2007-04-085753
McReynolds, Lisa J. ; Gupta, Sunny ; Figueroa, Maria ; Mullins, Mary C. ; Evans, Todd. / Smad1 and Smad5 differentially regulate embryonic hematopoiesis. In: Blood. 2007 ; Vol. 110, No. 12. pp. 3881-3890.
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