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DFG Research Training Group "TJ-Train" (GRK 2318/2)
Tight junctions and their proteins
Molecular features and actions in health and disease
Project
B1
1st period
2nd period
Prof. Dr. Thomas Willnow
& Dr.
Annette Hammes
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Max-Delbrück-Centrum für Molekulare Medizin (MDC),
Berlin-Buch
The endocytic receptor LRP2 serves as a central hub for dynamic cellular remodelling in neuronal stem cells and
neural crest cells in the developing neural tube
Background and previous work: The low density lipoprotein receptor
related protein 2 (LRP2) is a multifunctional endocytic receptor localized at the apical surface of polarized
epithelia. Patients with mutations in the LRP2 gene suffer amongst other congenital anomalies from neural
tube defects. LRP2 deficient mice consistently reflect disorders seen in humans. Our lab tries to understand the
mechanisms underlying the neural tube closure defects caused by LRP2 loss of function.
Our recent results indicate towards a crucial role of
LRP2 as a central hub in the periciliary compartment of neuroepithelial cells for establishing morphology,
polarity and ultimately specification of neuronal progenitors. We showed that LRP2 functionally interacts with
intracellular adaptor scaffold proteins and actin binding proteins that are involved in dynamic cell shape, apical
constriction and planar cell polarity, processes that are crucial for neural tube closure. Moreover, we identified
LRP2 in neural crest cells. Interestingly LRP2 deficient embryos show impaired cranial neural crest migration
patterns suggesting an important role of the receptor not only in neuroepithelial cell specification but also in
neural crest cell fate determination.
Hypothesis :
LRP2 functionally interacts with intracellular cellular scaffolds and thereby serves as a hub to regulate single
and collective cellular dynamics in polarized epithelia that involve rearrangements of the cytoskeleton and
cell-cell junctions, including tight junctions.
Aims, Work Plan and Methods:
At a cellular level we will try to understand the molecular and cell biological
LRP2 dependent mechanisms responsible for neuroepithelial cell polarity and apical constriction, a prerequisite
for proper neural tube formation. In addition, we will investigate the influence of LRP2 function on neural crest
cell motility and cell fate decisions. In specific, we will address how the endocytic receptor LRP2 and its
intracellular adaptor scaffold proteins affect cytoskeleton rearrangements and cell-cell connections and thereby
confer neural tube formation as well as directed migration of neural crest cells.
Using mouse models and ex vivo explant
cultures, we will employ various approaches based on molecular biology and imaging techniques. A strong focus will
be on high and super resolution imaging to characterize details in the interaction of cellular components in
neuroepithelial and neural crest cells. We are closely collaborating with project A4 (Martin Lehmann, Volker
Haucke) optimizing super resolution imaging (STED) on whole mount embryos and explant cultures.
Suggested reading: See Project-related publications, especially Refs. 1, 2, and 4
3rd cohort PhD doctoral student
Alessia Petrella
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2nd cohort PhD doctoral student
Sher Min Mak
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1st cohort PhD doctoral student
Izabela Kowalczyk
27.10.21: Doctoral examination scheduled
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Mecklenburg N*, Kowalczyk I*, Witte F* (*shared first authorship), Goerne J, Laier A, Mamo TM, Gonschior H, Lehmann M,
Richter M, Sporbert A, Purfuerst B, Hübner N, Hammes A (2021) Identification of novel disease relevant modulators of the SHH pathway in the developing brain.
Development
48(17): (17 pages) doi: 10.1242/dev.199307 (IF
6.9)
-
Kowalczyk I,
Lee C,
Schuster E,
Hoeren J,
Trivigno V,
Riedel L, Görne J,
Wallingford JB, Hammes A,
Feistel K (2021) Neural tube closure requires the
endocytic receptor Lrp2 and its functional interaction with intracellular scaffolds. Development
148(2): dev195008.
doi: 10.1242/dev.195008
(IF
6.9)
Project-related publications
If
a paper is not accessible, please mail to
.
-
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
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
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
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
Willnow TE, Christ A, Hammes A (2012) Endocytic receptor-mediated control of morphogen signaling.
Development
139: 4311-4319
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
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
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
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
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
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
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