NIH Research Festival
The brain and spinal cord of the central nervous system (CNS) is an immune privileged organ characterized by the absence of lymphatic vasculature and the presence of specialized endothelial cells (ECs) forming the blood-brain barrier (BBB). We aim to understand the link between the lymphatic avascularity and the BBB formation, and the molecular mechanisms that control these unique properties in the CNS vasculature.
The Prospero Homeobox-1 (Prox1) gene, master regulator of lymphatic vascular development, is transiently expressed in non-CNS ECs to produce lymphatic vessels forming loose cell-cell junctions. In contrast, CNS ECs form cell-cell tight junctions and the BBB, and do NOT express Prox1 in development and adulthood. These observations prompted us to hypothesize that CNS ECs tightly regulate Prox1 expression to maintain the lymphatic avascularity and BBB integrity.
To address effects of ectopic Prox1 expression in the CNS vasculature, we generated EC-specific Prox1 gain-of-function (GOF) mutants. The Prox1 GOF mutant embryonic brains showed severe abnormalities in the CNS vasculature, accompanied by the acquisition of a blood/lymphatic hybrid identity that was previously described in the Schlemm‚Äôs canal, a circular lymphatic-like vessel in the eye. Moreover, BBB disruption and severe leakage were found in the Prox1 GOF mutant vasculature at embryonic and postnatal stages, demonstrating that the ectopic Prox1 expression in CNS ECs induces BBB breakdown even when the barrier is mature.
Overall, our data provide the first evidence that tight regulation of Prox1 expression in CNS ECs is crucial for the formation and postnatal maintenance of the CNS-specific vascular properties.
Scientific Focus Area: Developmental Biology
This page was last updated on Monday, September 25, 2023