Abstract
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.
Highlights
The lymphatic system maintains tissue fluid balance, and dysfunction of lymphatic vessels and valves causes human lymphedema syndromes
Lymphatic endothelial cells emerge from the cardinal veins and migrate away to form the primary lymphatic vessels, that is, the lymph sacs, which get separated from the blood vasculature by lymphovenous valves[2,3,4]
We show that Cdk[5] plays an essential role in the regulation of lymphatic vessel development and valve formation
Summary
The lymphatic system maintains tissue fluid balance, and dysfunction of lymphatic vessels and valves causes human lymphedema syndromes. Endothelial-specific Cdk[5] knockdown causes congenital lymphatic dysfunction and lymphedema due to defective lymphatic vessel patterning and valve formation. We identify the transcription factor Foxc[2] as a key substrate of Cdk[5] in the lymphatic vasculature, mechanistically linking Cdk[5] to lymphatic development and valve morphogenesis. Cyclin-dependent kinase 5 (Cdk5), a proline-directed serine/ threonine kinase, does not drive cell cycle transitions though it belongs to the Cdk family As it exerts essential functions in the central nervous system (CNS) such as neuronal migration, axonal guidance and synaptic plasticity, and has been associated with neurodegenerative and neuropsychiatric diseases, Cdk[5] was thought to be neuron-specific for a long time[11]. A detailed investigation of a possible function of Cdk[5] in the endothelium in vivo is still lacking
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