The Left-Right Pitx2 Pathway Drives Organ-Specific Arterial and Lymphatic Development in the Intestine

Abstract

SUMMARY The dorsal mesentery (DM) is the major conduit for blood and lymphatic vessels in the gut. The mechanisms underlying their morphogenesis are challenging to study and remain unknown. Here we show that arteriogenesis in the DM begins during gut rotation and proceeds strictly on the left side, dependent on the Pitx2 target gene Cxcl12. Although competent Cxcr4-positive angioblasts are present on the right, they fail to form vessels and progressively emigrate. Surprisingly, gut lymphatics also initiate in the left DM and arise only after – and dependent on – arteriogenesis, implicating arteries as drivers of gut lymphangiogenesis. Our data begin to unravel the origin of two distinct vascular systems and demonstrate how early L-R molecular asymmetries are translated into organ-specific vascular patterns. We propose a dual origin of gut lymphangiogenesis, where prior arterial growth is required to initiate local lymphatics that only subsequently connect to the vascular system.

Pbx1 dependent control of VMC differentiation kinetics underlies gross renal vascular patterning

“…Notably, the gross architecture of an organ's vascular bed is essential for its physiological functions (Mahadevan et al, 2014), a relationship that is well illustrated in the kidney (Sequeira-Lopez and Gomez, 2011). Renal excretory functions are dependent on the delivery of 25% of cardiac output directly to the glomerular capillaries, which filter blood to remove waste.…”

Establishment of the Visceral Embryonic Midline Is a Dynamic Process that Requires Bilaterally Symmetric BMP Signaling

“…The two aortic tubes move medially and fuse in the midline ventral to the notochord ( Figures 1C, 1D, and 1H-1J). In parallel, the mesenchymal cells medial to the CE meet in the midline ventral to the aorta ( Figures 1I, 1I 0 , and 1I 00 ), forming the dorsal mesentery (DM) (Figures 1J, 1J 0 , and 1J 00 ), which plays an essential role in subsequent gut looping and morphogenesis (Davis et al, 2008;Mahadevan et al, 2014;Welsh et al, 2013). In summary, at the beginning of the process of ventral body wall formation the embryo is flat and the aorta and notochord are in direct contact with the endoderm.…”

Development of the lymphatic system: new questions and paradigms

“…Using lineage-tracing analyses, a cKit + hemogenic endothelium (HE) population was identified as the source of mesenteric LECs, indicating that non-venous lymphatics are derived from a naïve hematopoietic progenitor pool but not from definitive hematopoietic cells. Interestingly, Mahadevan et al (2014) also proposed that the mesenteric lymphatics arise from two populations of lymphatic progenitors: a venous population that originates in the wall of the subcardinal vein, and a non-venous population that arises in the left dorsal mesentery through an arteriogenesis-dependent process. In this case, paired-like homeodomain 2 (Pitx2) was shown to direct asymmetric arteriogenesis in the left dorsal mesentery only.…”

“…Consequently, the KO of Pitx2 resulted in specific elimination of the non-venous LEC progenitor pool. Nonetheless, the exact lineages of these two subsets of lymphatic progenitors have not yet been determined (Mahadevan et al, 2014).…”