Figure 4
Summary of leptin’s roles in the endocardial
cushion. During development, heart morphogenesis relies on Epithelial
to Mesenchymal Transformation (EMT), which is associated with a tightly
regulated cellular and molecular program. The spatiotemporal pattern of
leptin and leptin receptor depicts a pathway by which myocardial derived
leptin ligand engages with endocardial leptin receptors to drive EMT and
migration, consistent with the known cell autonomous pathway of cardiac
EMT. Utilizing an ex vivo assay to perform functional assays on mammalian
embryos, we demonstrated that loss of leptin abrogates adhesion, EMT and
migration and suggest that leptin mediates these processes via modulation
of Akt. The leptin pathway is independent of TGF-beta/Snail driven dissolution
of VE-cadherin. Interestingly, the specific effector molecules disrupted
by loss of leptin in the endocardial cushion are known mediators of adhesion,
migration and differentiation. Leptin’s role in adhesion of endocardial
cells within the cushion potentially occurs through alphavbeta3 integrin
receptor while leptin driven migration and invasion of mesenchymal cells
may be mediated by MMP-2. Further, MMPs modulate growth factor release
and receptor availability, therefore leptin induced protease activity
may not only promote matrix degradation and migration but also affect
morphogen gradients across the cardiac jelly and hence signaling cascades.
The potential branch points in the leptin signaling pathway and cross-talk
with other pathways remain to be uncovered. Ultimately leptin signaling
affects adhesion, EMT and migration within the embryonic heart.