Estrogen defines the dorsal-ventral limit of VEGF regulation to specify the location of the hemogenic endothelial niche

Kelli J. Carroll; Virginie Esain; Maija K. Garnaas; Mauricio Cortes; Michael C. Dovey; Sahar Nissim; Gregory M. Frechette; Sarah Y. Liu; Wanda Kwan; Claire C. Cutting; James M. Harris; Daniel A. Gorelick; Marnie E. Halpern; Nathan D. Lawson; Wolfram Goessling; Trista E. North

doi:10.1016/j.devcel.2014.04.012

Estrogen defines the dorsal-ventral limit of VEGF regulation to specify the location of the hemogenic endothelial niche

Kelli J. Carroll, Virginie Esain, Maija K. Garnaas, Mauricio Cortes, Michael C. Dovey, Sahar Nissim, Gregory M. Frechette, Sarah Y. Liu, Wanda Kwan, Claire C. Cutting, James M. Harris, Daniel A. Gorelick, Marnie E. Halpern, Nathan D. Lawson, Wolfram Goessling, Trista E. North

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

Abstract

Genetic control of hematopoietic stem and progenitor cell (HSPC) function is increasingly understood; however, less is known about the interactions specifying the embryonic hematopoietic niche. Here, wereport that 17β-estradiol (E2) influences production of runx1+ HSPCs in the AGM region by antagonizingVEGF signaling and subsequent assignment of hemogenic endothelial (HE) identity. Exposure toexogenous E2 during vascular niche developmentsignificantly disrupted flk1+ vessel maturation, ephrinB2+ arterial identity, and specification of scl+ HE by decreasing expression of VEGFAa and downstream arterial Notch-pathway components; heat shock induction of VEGFAa/Notch rescued E2-mediated hematovascular defects. Conversely, repression of endogenous E2 activity increased somitic VEGF expression and vascular target regulation, shifting assignment of arterial/venous fate and HE localization; blocking E2 signaling allowed venous production of scl+/runx1+ cells, independent of arterial identity acquisition. Together, these data suggest that yolk-derived E2 sets the ventral boundary of hemogenic vascular niche specification by antagonizing the dorsal-ventral regulatory limits of VEGF.

Original language	English (US)
Pages (from-to)	437-453
Number of pages	17
Journal	Developmental Cell
Volume	29
Issue number	4
DOIs	https://doi.org/10.1016/j.devcel.2014.04.012
State	Published - May 27 2014
Externally published	Yes

ASJC Scopus subject areas

Molecular Biology
General Biochemistry, Genetics and Molecular Biology
Developmental Biology
Cell Biology

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10.1016/j.devcel.2014.04.012

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Carroll, K. J., Esain, V., Garnaas, M. K., Cortes, M., Dovey, M. C., Nissim, S., Frechette, G. M., Liu, S. Y., Kwan, W., Cutting, C. C., Harris, J. M., Gorelick, D. A., Halpern, M. E., Lawson, N. D., Goessling, W., & North, T. E. (2014). Estrogen defines the dorsal-ventral limit of VEGF regulation to specify the location of the hemogenic endothelial niche. Developmental Cell, 29(4), 437-453. https://doi.org/10.1016/j.devcel.2014.04.012

Carroll, KJ, Esain, V, Garnaas, MK, Cortes, M, Dovey, MC, Nissim, S, Frechette, GM, Liu, SY, Kwan, W, Cutting, CC, Harris, JM, Gorelick, DA, Halpern, ME, Lawson, ND, Goessling, W & North, TE 2014, 'Estrogen defines the dorsal-ventral limit of VEGF regulation to specify the location of the hemogenic endothelial niche', Developmental Cell, vol. 29, no. 4, pp. 437-453. https://doi.org/10.1016/j.devcel.2014.04.012

@article{b5834f1e5b8243e48a26a6d45f62d59d,

title = "Estrogen defines the dorsal-ventral limit of VEGF regulation to specify the location of the hemogenic endothelial niche",

abstract = "Genetic control of hematopoietic stem and progenitor cell (HSPC) function is increasingly understood; however, less is known about the interactions specifying the embryonic hematopoietic niche. Here, wereport that 17β-estradiol (E2) influences production of runx1+ HSPCs in the AGM region by antagonizingVEGF signaling and subsequent assignment of hemogenic endothelial (HE) identity. Exposure toexogenous E2 during vascular niche developmentsignificantly disrupted flk1+ vessel maturation, ephrinB2+ arterial identity, and specification of scl+ HE by decreasing expression of VEGFAa and downstream arterial Notch-pathway components; heat shock induction of VEGFAa/Notch rescued E2-mediated hematovascular defects. Conversely, repression of endogenous E2 activity increased somitic VEGF expression and vascular target regulation, shifting assignment of arterial/venous fate and HE localization; blocking E2 signaling allowed venous production of scl+/runx1+ cells, independent of arterial identity acquisition. Together, these data suggest that yolk-derived E2 sets the ventral boundary of hemogenic vascular niche specification by antagonizing the dorsal-ventral regulatory limits of VEGF.",

author = "Carroll, {Kelli J.} and Virginie Esain and Garnaas, {Maija K.} and Mauricio Cortes and Dovey, {Michael C.} and Sahar Nissim and Frechette, {Gregory M.} and Liu, {Sarah Y.} and Wanda Kwan and Cutting, {Claire C.} and Harris, {James M.} and Gorelick, {Daniel A.} and Halpern, {Marnie E.} and Lawson, {Nathan D.} and Wolfram Goessling and North, {Trista E.}",

note = "Funding Information: We thank P. Crosier and K. Crosier for the runx1P1:eGFP line, S.W. Jin for the hs:VEGFAa line, and B. Paw, I. Drummond, C. Burns, and M. Lin for suggestions and reagents. This investigation was supported by an American Society of Hematology Scholar Award and a National Institute of Environmental Health Sciences R21 (to T.E.N.). K.J.C. is supported by a National Science Foundation Graduate Research Fellowship and a Harvard University Vranos Family Graduate Research Fellowship. ",

year = "2014",

month = may,

day = "27",

doi = "10.1016/j.devcel.2014.04.012",

language = "English (US)",

volume = "29",

pages = "437--453",

journal = "Developmental Cell",

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T1 - Estrogen defines the dorsal-ventral limit of VEGF regulation to specify the location of the hemogenic endothelial niche

AU - Carroll, Kelli J.

AU - Esain, Virginie

AU - Garnaas, Maija K.

AU - Cortes, Mauricio

AU - Dovey, Michael C.

AU - Nissim, Sahar

AU - Frechette, Gregory M.

AU - Liu, Sarah Y.

AU - Kwan, Wanda

AU - Cutting, Claire C.

AU - Harris, James M.

AU - Gorelick, Daniel A.

AU - Halpern, Marnie E.

AU - Lawson, Nathan D.

AU - Goessling, Wolfram

AU - North, Trista E.

N1 - Funding Information: We thank P. Crosier and K. Crosier for the runx1P1:eGFP line, S.W. Jin for the hs:VEGFAa line, and B. Paw, I. Drummond, C. Burns, and M. Lin for suggestions and reagents. This investigation was supported by an American Society of Hematology Scholar Award and a National Institute of Environmental Health Sciences R21 (to T.E.N.). K.J.C. is supported by a National Science Foundation Graduate Research Fellowship and a Harvard University Vranos Family Graduate Research Fellowship.

PY - 2014/5/27

Y1 - 2014/5/27

N2 - Genetic control of hematopoietic stem and progenitor cell (HSPC) function is increasingly understood; however, less is known about the interactions specifying the embryonic hematopoietic niche. Here, wereport that 17β-estradiol (E2) influences production of runx1+ HSPCs in the AGM region by antagonizingVEGF signaling and subsequent assignment of hemogenic endothelial (HE) identity. Exposure toexogenous E2 during vascular niche developmentsignificantly disrupted flk1+ vessel maturation, ephrinB2+ arterial identity, and specification of scl+ HE by decreasing expression of VEGFAa and downstream arterial Notch-pathway components; heat shock induction of VEGFAa/Notch rescued E2-mediated hematovascular defects. Conversely, repression of endogenous E2 activity increased somitic VEGF expression and vascular target regulation, shifting assignment of arterial/venous fate and HE localization; blocking E2 signaling allowed venous production of scl+/runx1+ cells, independent of arterial identity acquisition. Together, these data suggest that yolk-derived E2 sets the ventral boundary of hemogenic vascular niche specification by antagonizing the dorsal-ventral regulatory limits of VEGF.

AB - Genetic control of hematopoietic stem and progenitor cell (HSPC) function is increasingly understood; however, less is known about the interactions specifying the embryonic hematopoietic niche. Here, wereport that 17β-estradiol (E2) influences production of runx1+ HSPCs in the AGM region by antagonizingVEGF signaling and subsequent assignment of hemogenic endothelial (HE) identity. Exposure toexogenous E2 during vascular niche developmentsignificantly disrupted flk1+ vessel maturation, ephrinB2+ arterial identity, and specification of scl+ HE by decreasing expression of VEGFAa and downstream arterial Notch-pathway components; heat shock induction of VEGFAa/Notch rescued E2-mediated hematovascular defects. Conversely, repression of endogenous E2 activity increased somitic VEGF expression and vascular target regulation, shifting assignment of arterial/venous fate and HE localization; blocking E2 signaling allowed venous production of scl+/runx1+ cells, independent of arterial identity acquisition. Together, these data suggest that yolk-derived E2 sets the ventral boundary of hemogenic vascular niche specification by antagonizing the dorsal-ventral regulatory limits of VEGF.

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EP - 453

JO - Developmental Cell

JF - Developmental Cell

IS - 4

ER -

Estrogen defines the dorsal-ventral limit of VEGF regulation to specify the location of the hemogenic endothelial niche

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