Molecular pathways in forebrain development and holoprosencephaly

Project Leaders: Annette Hammes-Lewin e-mail / Thomas Willnow e-mail

 

Fusion of the forebrain hemispheres as in holoprosencephaly (HPE) is the most common anomaly of the human brain affecting 1 in 250 pregnancies. Several genes have been implicated in the etiology of HPE including LDL receptor-related protein (LRP) 2, an endocytic receptor mutated in autosomal recessive Donnai-Barrow syndrome. In the reporting period we clarified the molecular mechanism whereby LRP2 regulates forebrain development and why HPE ensues in patients with Donnai-Barrow syndrome. Thus, we identified LRP2 as a novel component of the sonic hedgehog (SHH) signaling machinery in the forebrain neuroepithelium. LRP2 acts as SHH binding protein that sequesters the morphogen in its target field and enables cellular signal transduction through patched 1 and smoothened. LRP2 deficiency in mice leads to failure of the neuroepithelium to respond to SHH and in defects in forebrain induction. Overexpression of LRP2 variants in cells enhances SHH signaling capacity. Our data substantiate the emerging concept that auxiliary receptors are critical modulators of morphogen delivery and signal reception in target tissues, and identified an important role for LRP2 in SHH action in the forebrain. Future work in this project aims at substantiating the relevance of LRP2 as part of the SHH receptorsome in developmental pathways of medical relevance including forebrain development and HPE, retina formation and retinopathies, as well as adult neurogenesis.