Mechanisms of Wnt ligand specific signaling in the development of blood-retina barrier and blood-brain barrier

Canonical Wnt signaling plays a crucial role in several vital processes, including neural tube and retinal vascularization, as well as the maintenance of the blood-brain barrier (BBB) and blood-retina barrier (BRB). Specifically, the Wnt signal triggered by Norrin has been identified as a key regulator of vascular development in

the vertebrate retina and is essential for regulating significant blood vessels in the ear. Norrin plays an essential role in the development and maintenance of the retina, which is the light-sensitive tissue at the back of the eye responsible for vision. Mutations or abnormalities in the Norrin gene can lead to various retinal diseases, like

Norrie disease which is characterized by abnormal development of the retina and other structures in the eye. When Frizzled receptor 4 (FZD4), the receptor of Norrin, is knocked out in mice, it leads to abnormal vascular development in the retina. TSPAN12 interacts with FZD4 and Norrin and acts as co-receptor that enhances

FZD4-meidted Norrin signaling. To ensure the integrity of the BBB and BRB, the involvement of two related Wnt signaling coreceptors, namely LDL receptor-related protein 5 (LRP5) and LRP6, collaborate with Norrin or Wnt to bind to the FZD, initiating the Wnt signaling pathway. Furthermore, disruptions in Norrin/FZD4 signaling in the

adult retina and cerebellum result in cell-autonomous changes in the BRB and BBB function, respectively, indicating a necessity for Norrin/FZD4 signaling in the maintenance of barriers and underscores the remarkable adaptability of the mature central nervous system's (CNS) vascular structure. Additionally, the integrity of the

BBB relies on the presence of Wnt7 and its co-receptors, RECK and GPR124. The combined action of these signaling molecules and receptors is essential for the proper functioning and maintenance of the BBB and BRB. Our main objective is to understand the molecular mechanisms by which Norrin, TSPAN12, RECK and GPR124

contribute to the ligand specific Wnt/-catenin signaling in retinal and CNS angiogenesis. To accomplish this, we will use recombinant receptor complexes to determine their molecular mechanisms of action by biochemical and biophysical approaches. Through our investigations, we seek to unravel the precise role of Norrin, Wnt7 and

their co-receptors in initiating signaling events. The results will have implications for the development of novel therapeutic strategies targeting retinal diseases and the maintenance of barrier functions in the CNS.