The blood vasculature instructs lymphatic patterning in a SOX7‐dependent manner

Author:

Chiang Ivy K N1,Graus Matthew S1,Kirschnick Nils2,Davidson Tara1,Luu Winnie1,Harwood Richard3,Jiang Keyi1,Li Bitong1ORCID,Wong Yew Yan4ORCID,Moustaqil Mehdi5,Lesieur Emmanuelle6,Skoczylas Renae6,Kouskoff Valerie7,Kazenwadel Jan8ORCID,Arriola‐Martinez Luis8,Sierecki Emma5ORCID,Gambin Yann5,Alitalo Kari9ORCID,Kiefer Friedmann2,Harvey Natasha L8,Francois Mathias14ORCID

Affiliation:

1. The Centenary Institute, David Richmond Program for Cardio‐Vascular Research: Gene Regulation and Editing, Sydney Medical School University of Sydney Sydney NSW Australia

2. European Institute for Molecular Imaging (EIMI) University of Münster Münster Germany

3. Sydney Microscopy and Microanalysis University of Sydney Sydney NSW Australia

4. The Genome Imaging Center The Centenary Institute Sydney NSW Australia

5. EMBL Australia Node in Single Molecule Science, and School of Medical Sciences University of New South Wales Sydney NSW Australia

6. Institute for Molecular Bioscience The University of Queensland St. Lucia QLD Australia

7. Division of Developmental Biology & Medicine The University of Manchester Manchester UK

8. Centre for Cancer Biology University of South Australia and SA Pathology Adelaide SA Australia

9. Wihuri Research Institute and Translational Cancer Medicine Program, Faculty of Medicine University of Helsinki Helsinki Finland

Abstract

AbstractDespite a growing catalog of secreted factors critical for lymphatic network assembly, little is known about the mechanisms that modulate the expression level of these molecular cues in blood vascular endothelial cells (BECs). Here, we show that a BEC‐specific transcription factor, SOX7, plays a crucial role in a non‐cell‐autonomous manner by modulating the transcription of angiocrine signals to pattern lymphatic vessels. While SOX7 is not expressed in lymphatic endothelial cells (LECs), the conditional loss of SOX7 function in mouse embryos causes a dysmorphic dermal lymphatic phenotype. We identify novel distant regulatory regions in mice and humans that contribute to directly repressing the transcription of a major lymphangiogenic growth factor (Vegfc) in a SOX7‐dependent manner. Further, we show that SOX7 directly binds HEY1, a canonical repressor of the Notch pathway, suggesting that transcriptional repression may also be modulated by the recruitment of this protein partner at Vegfc genomic regulatory regions. Our work unveils a role for SOX7 in modulating downstream signaling events crucial for lymphatic patterning, at least in part via the transcriptional repression of VEGFC levels in the blood vascular endothelium.

Funder

Australian Research Council

National Health and Medical Research Council

Publisher

Springer Science and Business Media LLC

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,Molecular Biology,General Neuroscience

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