Biology subjects

Kiefer, F.

Publications and source records attributed to Kiefer, F..

3 recordsLinked to original sources

bioRxiv2021

The blood vasculature instructs lymphatics patterning in a SOX7-dependent manner

Despite a growing catalogue 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 lymphatic vessel patterning by modulating the transcription of lymphangiocrine signals. While SOX7 is not expressed in lymphatic endothelial cells (LECs), 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 signalling events crucial for lymphatic patterning, at least in part via the transcriptional repression of VEGFC levels in the blood vascular endothelium.

developmental biology↗

bioRxiv2021

Vegfr3-tdTomato, a reporter mouse for microscopic visualization of lymphatic vessel by multiple modalities

Lymphatic vessels are indispensable for tissue fluid homeostasis, transport of solutes and dietary lipids and immune cell trafficking. In contrast to blood vessels, which are easily visible by their erythrocyte cargo, lymphatic vessels are not readily detected in the tissue context. Their invisibility interferes with the analysis of the three-dimensional lymph vessel structure in large tissue volumes and hampers dynamic intravital studies on lymphatic function and pathofunction. An approach to overcome these limitations are mouse models, which express transgenic fluorescent proteins under the control of tissue-specific promotor elements. We introduce here the BAC-transgenic mouse reporter strain Vegfr3-tdTomato that expresses a membrane-tagged version of tdTomato under control of Flt4 regulatory elements. Vegfr3-tdTomato mice inherited the reporter in a mendelian fashion and showed selective and stable fluorescence in the lymphatic vessels of multiple organs tested, including lung, kidney, heart, diaphragm, intestine, mesentery and dermis. In this model, tdTomato expression was sufficient for direct visualisation of lymphatic vessels by epifluorescence microscopy. Furthermore, lymph vessels were readily visualized using a number of microscopic modalities including confocal laser scanning, light sheet fluorescence and two-photon microscopy. Due to the early onset of VEGFR-3 expression in venous embryonic vessels and the short maturation time of tdTomato, this reporter offers an interesting alternative to Prox1-promoter driven lymphatic reporter mice for instance to study the developmental differentiation of venous to lymphatic endothelial cells.

cell biology↗

bioRxiv2020

p53 plays a central role in lymphatic anomalies

Activation of the transcription factor p53 has been associated with several developmental syndromes. In normal tissues, p53 is kept at very low undetectable physiological levels. When triggered by cellular stressors, p53 prompts important anti-proliferative and apoptotic programs part of its tumor suppressor activity or as the guardian of tissue homeostasis. We generated two murine models that display cutaneous hemorrhaging, severe edema, and distended blood-filled lymphatic vessels at late-gestation due to overactive p53 uniquely affecting lymphatic endothelial cells during development. Overactive p53 operated distinctively through anti-proliferative route in this tissue resulting in a decrease in initial lymphatics that normally absorb interstitial fluid. Remarkably, genetic or pharmacologic normalization of p53 restored lymphatic homeostasis and reversed lymphatic phenotypes. In parallel, several human lymphatic disease tissues exhibited high p53 levels exclusively in the lymphatic endothelium while p53 remained undetectable in surrounding arterial or venous vessels. We report here, for the first time, an extended role that the p53 pathway plays in the genesis of lymphatic homeostasis deficiencies opening the way for new therapeutic avenues for these rare, poorly understood, and incurable lymphatic maladies.

developmental biology↗