Fig. 7. Summary and a model for Ltbp1L requirement in the septating OFT. (A) Cardiac neural crest cells (CNCCs; orange) initially (E9.5-10.5) express genes necessary for proper specification, delamination and migration. As CNCCs relocate to the outflow tract (OFT) at E11.5, their gene expression program changes (blue CNCCs). This reprogramming correlates with morphological changes, such as aortico-pulmonary (AP) septum formation, remodeling of pharyngeal arch arteries (PAAs) and differentiation into smooth muscle cells (SMCs). At E12.5, CNCCs continue their gene expression program (blue cells) that enables them to elongate the AP septum, to continue remodeling PAAs and to differentiate into SMCs. Ltbp1L^-/- CNCCs are normal and have a migratory trajectory undistinguishable from control littermates. The gene expression pattern characteristic for the migrating CNCCs also appears normal in Ltbp1L^-/- embryos (orange CNCCs). However, when CNCCs invade the ECM in the OFT of Ltbp1L nulls, their gene expression program and function alters (E11.5, green CNCCs rather than blue) because they fail to form the AP septum. At E12.5, other morphological changes are evident - remodeling of defective PAAs and AP septum absence. However, CNCCs in Ltbp1L nulls successfully differentiate into SMCs. (B) Functional Tgf-ß signaling is required for the maintenance of the appropriate gene expression program and function of post-migratory CNCCs. The ECM of the OFT contains both Ltbp1L-LLC and Ltbp3-LLC. Post-migratory CNCCs specifically recognize Ltbp1L-LLC and activate the latent Tgf-ß. When the extracellular matrix (ECM) of the OFT is deprived of Ltbp1L, post-migratory CNCCs do not sufficiently propagate Tgf-ß signals and, therefore, do not express genes required for their proper function (green CNCCs), resulting in persistent truncus arteriosus (PTA). Ltbp3 cannot substitute for Ltbp1L function, because post-migratory CNCCs do not recognize and act on Ltbp3-LLC.