DFG Research Training Group "TJ-Train" (GRK 2318)
Tight junctions and their proteins
Molecular features and actions in health and disease

Project B1

Prof. Dr. Thomas Willnow      &    Dr. Annabel Christ 

Max-Delbrück-Centrum für Molekulare Medizin (MDC),
Berlin-Buch

Neuroepithelial barrier function in brain development

Neuroepithelial progenitor cells (NPCs) are stem cells that give rise to the various cell types of the developing brain. During neurulation, NPCs establish the neural tube, the precursor to the mammalian CNS. Proper maintenance of cell polarity and function is essential to control proliferative versus neurogenic divisions of NPCs, and to govern morphological events that transform the neural tube into brain and spinal cord. In this PhD project, we will study the sonic hedgehog (SHH) pathway, a morphogen pathway crucial for control of NPC specification. Specifically, we will characterize a novel class of auxiliary SHH receptors essential for morphogen signalling in NPCs, and why defects in these receptors cause holoprosencephaly, the most common forebrain anomaly in humans.

To do so, we will follow two experimental strategies, namely transgenic mouse models as well as human induced pluripotent stem cells (iPSCs). Firstly, the PhD candidate will study established mouse models carrying single or combined SHH receptor gene defects. Using in situ hybridization and immunohistology on whole mounts and tissue explants, he/she will dissect the roles played by each receptor in vivo, and how they interact in SHH signaling during brain development. Secondly, he/she will differentiate human iPSCs carrying inherited mutations in SHH receptor genes into NPCs, and study why these mutations cause neuroepithelial structure and function detects. This latter approach will include the analysis of SHH signal transduction processes at the molecular level using advanced imaging and single cell sequencing techniques.

Suggested reading:  See Project-related publications, especially Refs. 1, 2, and 4

PhD doctoral student

  • Izabela Kowalczyk

Project-related publications

If a paper is not accessible, please mail to  

  1. Christ A, Herzog K, Willnow TE (2016) LRP2, an auxiliary receptor that controls sonic hedgehog signaling in development and disease. Dev. Dyn. 245(5): 569-579 

  2. Christ A, Christa A, Klippert J, Eule JC, Bachmann S, Wallace VA, Hammes A, Willnow TE (2015) LRP2 acts as SHH clearance receptor to protect the retinal margin from mitogenic stimuli. Dev. Cell 35: 36-48

  3. Breiderhoff T, Himmerkus N, Stuiver M, Mutig K, Will C, Meij IC, Bachmann S, Bleich M, Willnow TE, Müller D (2012) Deletion of caudin-10 (Cldn10) in the thick ascending limb impairs paracellular sodium permeability and leads to hypermagnesemia and nephrocalcinosis. Proc. Natl. Acad. Sci. USA 109: 14241-14246

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

  5. Willnow TE, Christ A, Hammes A (2012) Endocytic receptor-mediated control of morphogen signaling. Development 139: 4311-4319

  6. Kur E, Christa A, Veth KN, Gajera CR, Andrade-Navarro MA, Zhang J, Willer JR, Gregg RG, Abdelilah-Seyfried S, Bachmann S, Link BA, Hammes A, Willnow TE (2011) Loss of Lrp2 in zebrafish disrupts pronephric tubular clearance but not forebrain development. Dev. Dyn. 240: 1567-1577

  7. Christ A, Terryn S, Schmidt V, Christensen EI, Huska MR, Andrade-Navarro MA, Hübner N, Devuyst O, Hammes A, Willnow TE (2010) The soluble intracellular domain of megalin does not affect renal proximal tubular function in vivo. Kidney Int. 78: 473-477

  8. Gajera CR, Emich H, Lioubinski O, Christ A, Beckervordersandforth-Bonk R, Yoshikawa K, Bachmann S, Christensen EI, Götz M, Kempermann G, Peterson AS, Willnow TE, Hammes A (2010) Ependymal cells regulate BMP signaling in the adult neurogenic niche through LRP2. J. Cell. Sci. 123: 1922-1930

  9. Zhang J, Piontek J, Wolburg H, Piehl C, Liss M, Otten C, Christ A, Willnow TE, Blasig IE, Abdelilah-Seyfried S (2010) Estabilshment of a neuroepithelial barrier by claudin5a is essential for zebrafish brain ventricular lumen expansion. Proc. Natl. Acad. Sci. USA 107: 1425-1430

  10. Anzenberger U, Dehmel B, Bit-Avragim N, Rohr S, Willnow TE, Abdelilah-Seyfried S (2006) Elucidation of Megalin/LRP2-dependent endocytic transport processes in the larval zebrafish pronephros. J. Cell Sci. 119: 2127-2137

  11. Hammes A, Andreassen TK, Spoelgen R, Raila J, Huebner N, Schulz H, Metzger J, Schweigert F J, Luppa PB, Nykjaer A, Willnow TE (2005) Impaired development of the reproductive organs in mice lacking megalin, an endocytic receptor for steroid hormones. Cell 122: 751-762