Helmholtz Fellow

An emerging concept in developmental biology suggests that auxiliary receptors and surface binding sites are critical modulators of morphogen delivery and signaling in target tissues. In support of this hypothesis, I recently identified the endocytic receptor LRP2 as co-receptor essential for sonic hedgehog (SHH) signaling in the developing nervous system, and I uncovered the mechanisms underlying forebrain anomalies in patients with hereditary LRP2 gene defects. My project aims at deciphering the fundamental principles of this novel morphogen receptor pathway at the molecular detail. My results will not only advance our understanding of common human brain malformations but possibly also of SHH functions in other areas of medical relevance such as adult neurogenesis and tumor formation.

In a new study I could show that in the developing retina LRP2 mediates endocytic clearance of SHH to antagonize morphogen action. LRP2-mediated clearance prevents spread of SHH activity from the central retina into the retinal margin to protect quiescent progenitor cells in this niche from mitogenic stimuli. Loss of LRP2 in mice increases the sensitivity of the retinal margin for SHH, causing expansion of the retinal progenitor cell pool and hyperproliferation of this tissue. These new findings document the ability of LRP2 to act, in a context dependent manner, as activator or inhibitor of the SHH pathway. Furthermore, this study uncovered LRP2 activity as the molecular mechanism imposing quiescence of the retinal margin in the mammalian eye, and suggest SHH-induced proliferation of the retinal margin as molecular cause of buphthalmos in mouse models and patients with LRP2 defects.

Team

PhD student:                 Lena Bunatyan

Technical Assistant:      Melanie Liekweg

Publications relevant to this proposal

1. Christ, A., Christa, A., Klippert, J., Eule, J.C., Bachmann, S., Wallace, V.A., Hammes, A. and T.E. Willnow. (2015). LRP2 Acts as SHH Clearance Receptor to Protect the Retinal Margin from Mitogenic Stimuli. Developmental Cell 35: 1-13.

2. Cases, O., Joseph, A., Obry, A., Santin, M.D., Ben-Yacoub, S., Paques, M., Amsellem-Levera, S., Bribian, A., Simonutti, M., Augustin, S., Debeir, T., Sahel, J.A., Christ, A., de Castro, F., Lehéricy, S., Cosette, P. and R. Kozyraki. (2015). Foxg1-Cre Mediated Lrp2 Inactivation in the Developing Mouse Neural Retina, Ciliary and Retinal Pigment Epithelia Models Congenital High Myopia. PLoS One 10(6): e0129518.

3. Willnow, T.E., Christ, A., and A. Hammes. (2012). Endocytic receptor-mediated control of morphogen signaling. Development 139: 4311-4319.

4. Christ, A., Christa, A., Kur, E., Lioubinski, O., Bachmann, S., Willnow, T.E., and A. Hammes. (2012). LRP2 is an auxiliary SHH receptor required to condition the forebrain ventral midline for inductive signals. Developmental Cell 22(2): 268-278.

5. Christ, A., Terryn, S., Schmidt, V., Christensen, E.I., Huska, M.R., Andrade-Navarro, M.A., Hübner, N., Devuyst, O., Hammes, A., and T. E. Willnow. (2010). The soluble intracellular domain of megalin does not affect renal proximal tubular function in vivo. Kidney International 78(5): 473-7.

6. Gajera, C.R., Emich, H., Lioubinski, O., Christ, A., Beckervordersandforth-Bonk, R., Yoshikawa, K., Bachmann, S., Christensen, E.I., Götz, M., Kempermann, G., Peterson, A.S., Willnow, T.E. and A. Hammes. (2010). Ependymal cells regulate BMP signaling in the adult neurogenic niche through LRP2 Journal of Cell Science 123: 1922-30.