Balancing Sonic hedgehog Signaling in Health and Disease of the Brain
Cell Biology
Final Report Abstract
Embryonic neural development but also adult neurogenesis are processes dependent on the interplay of different signaling pathways. The tight regulation of pathway functions and the precise timing of their activity ensures correct patterning of the CNS and ongoing neurogenesis in the adult brain. Defects in these morphogenetic processes lead to developmental abnormalities in the brain resulting in a spectrum of severe forebrain malformations referred to as holoprosencephaly (HPE) but also a disturbed balance of proliferative cell fate decisions in stem and progenitor cell populations implicated in adult neurogenesis. LRP2 is an endocytic receptor of the family of low-density lipoprotein receptorrelated proteins (LRPs), multifunctional cell surface receptors that bind and endocytose ligands with diverse biological functions. LRP2 has been identified as a co-receptor for SHH in control of morphogen signaling during embryogenesis. Specifically, LRP2, but also other SHH binding proteins like CDON and GAS1, act as co-receptors to the classical SHH receptor Patched (PTCH) 1. Their activities are essential to activate the full spectrum of SHH pathway functions during development and adult tissue homeostasis, yet the molecular mechanisms of their action remained elusive. Using novel transgenic mouse lines and induced pluripotent stem cell-based cell models, we showed that SHH co-receptor LRP2, CDON, and GAS1 also play major roles in other signal transduction pathways during brain development. We identified interaction of LRP2 and CDON to active NODAL signaling during early patterning processes, needed for activation of SHH signaling in the rostral embryonic neuroepithelium. We also showed that GAS1 function is not limited to the SHH pathway but is also required for promoting NOTCH signaling during neuroepithelial differentiation. Loss of GAS1 results in defects in NOTCH-dependent facilitation of SHH signaling, leading to a failure in maintaining the SHH activity domain in the rostral ventral neuroepithelium, ultimately resulting in HPE. Furthermore, we classified LRP2 also as novel component of the planar cell polarity pathway in coordination of motile cilia function in the adult ependyma preserving brain homeostasis and adult neurogenesis. Taken together, we uncovered unique roles for SHH co-receptors LRP2, CDON and GAS1 in morphogenetic processes during forebrain development and adult brain homeostasis by acting as a molecular interface in integrating different signaling pathways from SHH, NOTCH, Nodal, and PCP.
Publications
- Cdon mutation and fetal alcohol converge on Nodal signaling in a mouse model of holoprosencephaly. Elife. Sep 2020 2;9
Mingi Hong, Annabel Christ, Anna Christa, Thomas E. Willnow, Robert S. Krauss
(See online at https://doi.org/10.7554/elife.60351) - GAS1 is required for NOTCH-dependent facilitation of SHH signaling in the ventral forebrain neuroepithelium. Development, Sep 2021
Marczenke, M., Sunaga-Franze, D.Y., Popp, O., Althaus, I., Sauer, S., Mertins, P., Christ, A., Allen, B.L. and Willnow, T.E.
(See online at https://doi.org/10.1242/dev.200080) - LRP2 contributes to planar cell polarity-dependent coordination of motile cilia function
Lena Bunatyan, Anca Margineanu, Camille Boutin, Mireille Montcouquiol, Sebastian Bachmann, Erik Ilsø Christensen, Thomas E. Willnow, and Annabel Christ
(See online at https://doi.org/10.1101/2022.07.12.499714)
