Pkd1 Regulates Lymphatic Vascular Morphogenesis during Development

Coxam, Baptiste; Sabine, Amélie; Bower, Neil I.; Smith, K. A.; Pichol-Thievend, Cathy; Skoczylas, Renae; Astin, Jonathan W.; Frampton, Emmanuelle; Jaquet, Muriel; Crosier, Philip S.; Parton, Robert G.; Harvey, Natasha L.; Petrova, Tatiana V.; Schulte‐Merker, Stefan; François, Mathias; Hogan, Benjamin M.

doi:10.1016/j.celrep.2014.03.063

Cited by 83 publications

(107 citation statements)

References 49 publications

(78 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…RNA was extracted, amplified and cDNA was synthesized as previously described (Coxam et al, 2014;Picelli et al, 2014). Primer sequences and details of the quantitative PCR analysis are provided in the supplementary Materials and Methods.…”

Section: Fluorescence-activated Cell Sorting (Facs) and Expression Anmentioning

confidence: 99%

SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development

et al. 2017

Self Cite

View full text Add to dashboard Cite

Arterial specification and differentiation are influenced by a number of regulatory pathways. While it is known that the Vegfa-Notch cascade plays a central role in this biological process, the transcriptional hierarchy controlling arterial specification has not been fully delineated. To elucidate the direct transcriptional regulators of Notch receptor expression in arterial endothelial cells, we used histone signatures, DNaseI hypersensitivity and ChIP-seq data to identify enhancers for the human NOTCH1 and zebrafish notch1b genes. These enhancers were able to direct arterial endothelial cell-restricted expression in transgenic models. Genetic disruption of SOXF binding sites clearly established a requirement for members of the SOXF group of transcription factors (SOX7,-17 and-18) to drive these enhancers activity in vivo. Further, endogenous deletion of the notch1b enhancer led to a significant augmentation of arterio-venous defects in notch-pathway deficient zebrafish. Loss of SoxF function revealed that these factors are necessary for the activity of NOTCH1 and notch1b enhancers, and for correct endogenous Notch1 gene transcription. These findings therefore position SOXF transcription factors directly upstream of Notch receptor expression during the acquisition of arterial identity in vertebrates.

show abstract

Section: Fluorescence-activated Cell Sorting (Facs) and Expression Anmentioning

confidence: 99%

SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…5). This points to a specific function of Cdk5 in the lymphatic vasculature, like many genes that exert a tissue specific role, despite showing a wide expression pattern, for example, Rb for retinoblastoma 22 or Pkd1 for lymphatic vasculature 23,24 .…”

Section: Resultsmentioning

confidence: 99%

Cdk5 controls lymphatic vessel development and function by phosphorylation of Foxc2

et al. 2015

View full text Add to dashboard Cite

The lymphatic system maintains tissue fluid balance, and dysfunction of lymphatic vessels and valves causes human lymphedema syndromes. Yet, our knowledge of the molecular mechanisms underlying lymphatic vessel development is still limited. Here, we show that cyclin-dependent kinase 5 (Cdk5) is an essential regulator of lymphatic vessel development. Endothelial-specific Cdk5 knockdown causes congenital lymphatic dysfunction and lymphedema due to defective lymphatic vessel patterning and valve formation. We identify the transcription factor Foxc2 as a key substrate of Cdk5 in the lymphatic vasculature, mechanistically linking Cdk5 to lymphatic development and valve morphogenesis. Collectively, our findings show that Cdk5-Foxc2 interaction represents a critical regulator of lymphatic vessel development and the transcriptional network underlying lymphatic vascular remodeling.

show abstract

“…Alternatively, there may be intrinsic defects in the vasculature, as has been reported in the skin lymphatics in Pkd1-null and Pkd2-null mice, 22 which may explain why the effects of VEGFC are more prominent in Pkd1 nl/nl mice than Cys1 cpk/cpk . Other studies have also demonstrated a role for Pkd1 in zebrafish lymphatic vessel morphogenesis 23 Future experiments should investigate VEGFC and other vascular growth factors perhaps in combination with epithelially targeted treatments. Ideally, these studies should include a slow-onset orthologous PKD1 model such as the Pkd1 RC/RC mouse, 24 since both of the models examined here progress very quickly, which did not allow the examination of multiple stages of cyst initiation, progression and end-stage PKD.…”

mentioning

confidence: 89%

Vascular Endothelial Growth Factor C for Polycystic Kidney Diseases

Huang¹,

Woolf

Kolatsi-Joannou³

et al. 2016

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Polycystic kidney diseases (PKD) are genetic disorders characterized by progressive epithelial cyst growth leading to destruction of normally functioning renal tissue. Current therapies have focused on the cyst epithelium, and little is known about how the blood and lymphatic microvasculature modulates cystogenesis. Hypomorphic Pkd1 nl/nl mice were examined, showing that cystogenesis was associated with a disorganized pericystic network of vessels expressing platelet/endothelial cell adhesion molecule 1 and vascular endothelial growth factor receptor 3 (VEGFR3). The major ligand for VEGFR3 is VEGFC, and there were lower levels of Vegfc mRNA within the kidneys during the early stages of cystogenesis in 7-day-old Pkd1 nl/nl mice. Seven-day-old mice were treated with exogenous VEGFC for 2 weeks on the premise that this would remodel both the VEGFR3 + pericystic vascular network and larger renal lymphatics that may also affect the severity of PKD. Treatment with VEGFC enhanced VEGFR3 phosphorylation in the kidney, normalized the pattern of the pericystic network of vessels, and widened the large lymphatics in Pkd1 nl/nl mice.These effects were associated with significant reductions in cystic disease, BUN and serum creatinine levels. Furthermore, VEGFC administration reduced M2 macrophage pericystic infiltrate, which has been implicated in the progression of PKD. VEGFC administration also improved cystic disease in Cys1 cpk/cpk mice, a model of autosomal recessive PKD, leading to a modest but significant increase in lifespan. Overall, this study highlights VEGFC as a potential new treatment for some aspects of PKD, with the possibility for synergy with current epithelially targeted approaches.

show abstract

Pkd1 Regulates Lymphatic Vascular Morphogenesis during Development

Cited by 83 publications

References 49 publications

SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development

SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development

Cdk5 controls lymphatic vessel development and function by phosphorylation of Foxc2

Vascular Endothelial Growth Factor C for Polycystic Kidney Diseases

Contact Info

Product

Resources

About