MAFB modulates the maturation of lymphatic vascular networks in mice

Abstract

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 coordinated 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.

Transcription Factor Control of Lymphatic Quiescence and Maturation of Lymphatic Neovessels in Development and Physiology

“…This is a developing area of interest to many, results from a recent publication by Hernández Vásquez et al (2021) compared the expression profiles of dermal capillary LECs to collecting vessel LECs in adult mice. This work identified several noteworthy genes of interest, including FOXP2 (discussed later) as a major regulator of collecting vessels morphology, whereas LYVE-1, MAF and CXCL12 were all significantly enriched in lymphatic capillaries, consistent with a more activated/sprouting phenotype ( Rondon-Galeano et al, 2020 ; Hernández Vásquez et al, 2021 ). Furthermore heterogeneity is apparent between lymphatic vessels from different tissue bed, but less is known about the heterogeneity within a specific vessel bed.…”

“…Transcriptomic analysis indicated MAFB is involved in the early induction of SOX18 expression, thus impacting PROX1 production through this signalling pathway ( Dieterich et al, 2015 ). This work was followed up by Rondon-Galeano et al (2020) , using a CRIPSR/Cas9 mouse model, these mice had a perinatal death associated with cyanosis. Upon investigation, dermal lymphatics in these mice had mild and transient delay in development.…”

“…Upon investigation, dermal lymphatics in these mice had mild and transient delay in development. However, in the diaphragm, MAFB was necessary for patterning the lymphatics that developed in the mutant mice were broader and covered a larger area of the diaphragm ( Rondon-Galeano et al, 2020 ). Other elements of the signalling cascade linked to MAFB include PROX1, LYVE1 and podoplanin.…”

The Mafb cleft‐associated variant H131Q is not required for palatogenesis in the mouse

“…The N‐terminus is only present in the large MAF proteins and contains a transcriptional activation domain inducing MAF target gene transcription by recruiting other transcriptional regulators. The large MAFs have been implicated in a variety of differentiation processes, during development of gonads, hematopoietic and lymphatic systems, hindbrain, pancreatic islets, kidney, and ectoderm 18‐26 …”

“…The etiologic gene of this mutation was later determined to be Mafb , 18 which has since been described extensively in the development of the hindbrain as a controller of rhombomere segmentation and cardiac neural crest cell migration 28,29 . Multiple murine alleles have been generated over the years, including complete loss of function, 24,26 several tissue‐specific deletions, 30,31 overexpression of Mafb , 32 and an allele harboring a human variant 33 . Mafb loss‐of‐function leads to neonatal lethality due to respiratory failure, 22 failure of renal development and macrophage differentiation 22,24 .…”