Podoplanin and CLEC-2 drive cerebrovascular patterning and integrity during development.

Area of Science:

• Neuroscience
• Developmental Biology
• Hematology

Background:

• C-type-lectin-like receptor 2 (CLEC-2) deficiency in mice leads to mid-gestation brain hemorrhages.
• Podoplanin, expressed on the developing neural tube, is a potential endogenous ligand for CLEC-2.

Purpose of the Study:

• To investigate the role of the podoplanin-CLEC-2 interaction in embryonic brain vascular development and hemorrhage prevention.
• To elucidate the mechanism by which podoplanin and CLEC-2 maintain vascular integrity.

Main Methods:

• Generation of podoplanin-deficient mice (podoplanin(fl/fl) crossed with PGK-Cre).
• 3D light-sheet microscopy, immunofluorescence, and electron microscopy to analyze cerebral vasculature.
• Analysis of platelet function and cell-cell connections in developing embryos.

Main Results:

• Absence of podoplanin or CLEC-2 resulted in tortuous and aberrantly patterned cerebral vessels by embryonic day 10.5.
• Widespread brain hemorrhages were observed by embryonic day 11.5 in deficient embryos.
• Defective pericyte recruitment and aberrant connections between endothelial cells, pericytes, and neuro-epithelial cells were identified.

Conclusions:

• Podoplanin on the neuro-epithelium interacts with platelet CLEC-2 to mediate platelet adhesion, aggregation, and secretion.
• This interaction is essential for guiding vascular maturation and integrity during embryonic development.
• The novel podoplanin-CLEC-2 pathway is critical for preventing embryonic cerebral hemorrhage.