MAFB modulates the maturation of lymphatic vascular networks in mice

• Published in: Developmental dynamics Vol. 249; no. 10; pp. 1201 - 1216
• Main Authors: Rondon‐Galeano, Maria, Skoczylas, Renae, Bower, Neil I., Simons, Cas, Gordon, Emma, Francois, Mathias, Koltowska, Katarzyna, Hogan, Benjamin M.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.10.2020; Wiley Subscription Services, Inc
• Subjects: Cell differentiation; Cell migration; CRISPR; Cyanosis; Dermis; development; Diaphragm; Embryos; Endothelial cells; Genetic modification; Genome editing; Homeostasis; Immune system; Lethality; lymphangiogenesis; lymphatic; Lymphatic system; MAFB; Maturation; Morphogenesis; Muscles; Mutants; Network formation; Redundancy; Rodents; Smooth muscle; Transcription factors; vascular; Vascular endothelial growth factor receptors; Veins & arteries; lymphangiogenesis; development; MAFB; vascular; lymphatic
• ISSN: 1058-8388; 1097-0177
• DOI: 10.1002/dvdy.209

Background Lymphatic vessels play key roles in tissue fluid homeostasis, immune cell trafficking and in diverse disease settings. Lymphangiogenesis requires lymphatic endothelial cell (LEC) differentiation, proliferation, migration, and co‐ordinated network formation, yet the transcriptional regulators underpinning these processes remain to be fully understood. The transcription factor MAFB was recently identified as essential for lymphangiogenesis in zebrafish and in cultured human LECs. MAFB is activated in response to VEGFC‐VEGFR3 signaling and acts as a downstream effector. However, it remains unclear if the role of MAFB in lymphatic development is conserved in the mammalian embryo. Results We generated a Mafb loss‐of‐function mouse using CRISPR/Cas9 gene editing. Mafb mutant mice presented with perinatal lethality associated with cyanosis. We identify a role for MAFB in modifying lymphatic network morphogenesis in the developing dermis, as well as developing and postnatal diaphragm. Furthermore, mutant vessels displayed excessive smooth muscle cell coverage, suggestive of a defect in the maturation of lymphatic networks. Conclusions This work confirms a conserved role for MAFB in murine lymphatics that is subtle and modulatory and may suggest redundancy in MAF family transcription factors during lymphangiogenesis. Key Findings We generate a novel MafB loss-of-function mouse model using CRISPR genome editing. MafB plays a conserved role in developmental lymphangiogenesis. MafB modulates lymphatic vascular network morphogenesis in the developing dermis and postnatal diaphragm. This work identified MafB as an important developmental transcription factor in vascular network formation.