Convergent evolution of scavenger cell development at brain borders.

Area of Science:

• Neuroimmunology
• Developmental Biology
• Evolutionary Biology

Background:

• The vertebrate central nervous system is protected by the blood-brain barrier and meningeal membranes, ensuring immune privilege.
• Microglia and border-associated macrophages (BAMs) in mammals perform immune surveillance and waste scavenging within the brain.
• The evolutionary origins of immune cell diversity and function, particularly scavenger cells at the central nervous system borders, remain unclear.

Purpose of the Study:

• To identify specific markers and regulators of mural lymphatic endothelial cell (muLEC) differentiation and maintenance.
• To investigate the evolutionary relationship between muLECs and mammalian BAMs.
• To understand the role of osr2 in muLEC function and the evolution of meningeal scavenger cells.

Main Methods:

• Identification and characterization of the transcription factor odd-skipped related 2 (osr2) in zebrafish.
• Analysis of osr2's role in muLEC differentiation and transition to scavenger cells, including its regulation of cadherin-6.
• Comparative analysis of osr2, lymphatic endothelial cell (LEC), and BAM markers across diverse vertebrate species.

Main Results:

• The transcription factor osr2 was identified as a specific marker and regulator of muLEC differentiation and maintenance in zebrafish.
• osr2 controls muLEC transition from interconnected endothelial cells to individual scavenger cells, partly via cadherin-6 regulation.
• muLECs share transcriptional similarities and functions with mammalian BAMs but are not homologous, indicating convergent evolution.
• Analysis across species revealed muLECs as an ancient lineage and BAMs as a recent mammalian specialization.

Conclusions:

• muLECs in zebrafish function as scavenger cells at the central nervous system borders, a role analogous to mammalian BAMs.
• The transcription factor osr2 is crucial for muLEC development and function, highlighting the plasticity of LECs in generating specialized cell types.
• The findings demonstrate that muLECs represent an ancient cell lineage, while BAMs are a more recent mammalian evolutionary development, showcasing convergent evolution in meningeal scavenger cell function.