PATHPATT

GREB1L is a causative gene of a spectrum of human congenital defects, including renal agenesis. Yet the encoded protein is poorly characterised. Since the pathophysiology of congenital defects cannot be assessed in patients, it is essential to trace back origins in the embryo and identify the cellular context of the disease gene. We aim to test the hypothesis that GREB1L, as a known target of the morphogen retinoic acid, regulates mesoderm patterning, a prerequisite for organogenesis. Supported by preliminary data, our specific objectives are to define the molecular network in which GREB1L functions, dissect developmental mechanisms regulated by GREB1L in the posterior and cardiac mesoderm and investigate relevance to patients with a poorly understood heart malformation, criss-cross heart. Using an exceptional patient cohort, a unique mouse model and cutting-edge technologies in omics, organoids and quantitative 3D imaging, the PATHPATT project will provide novel insights into fundamental mechanisms of embryo patterning and retinoic acid signaling, while deciphering pathophysiological processes in the heart and kidney, potentially relevant to a broader spectrum of congenital defects. The consortium combines interdisciplinary expertise at the forefront of developmental biology, paediatric cardiology and human genetics, to comprehensively address the pathophysiology of congenital defects.