Project 7

Elucidation of the functional role of Gpr126 during heart development

Felix B. Engel, University of Erlangen-Nürnberg

Team members
Gentian Musa

Project Description
Gpr126 belongs to the large class of seven-transmembrane spanning (7TM) Adhesion-type G protein-coupled receptors (aGPCR). 7TM receptors have proven the linchpin for countless physiological functions and a treasure trove for modern pharmaceutical intervention. aGPCR appear in stark contrast to the rest of the 7TM receptor superfamily. Despite their abundance, remarkable size and molecular structure facilitating cell and matrix contacts in a variety of organ systems, aGPCR are by far the most poorly understood 7TM receptor class. They possess large N termini containing various functional domains. In addition, many of them are autoproteolytically cleaved at their GPS sites into an N-terminal fragment (NTF) and C-terminal fragment. However, neither the general biological and pharmacological properties of aGPCR are known, nor have they been utilized yet in biomedicine.

Previously, we have demonstrated that Gpr126 function is required for cardiac development. Gpr126 deletion or knockdown causes mitochondrial dysfunction and ventricular hypertrabeculation in mice and zebrafish. With the help of domain-specific morpholinos in zebrafish, rescue experiments in Gpr126-depleted morphants and an in situ protein binding assay using mGpr126-NTF on mouse tissue sections, we have demonstrated that the NTF fragment of Gpr126 is important for cardiac trabeculation. Our data suggested that mGpr126-NTF acts in a paracrine fashion. However, the molecular mechanism utilized by Gpr126 to regulate heart development remains elusive.

Thus we currently work on the following questions:

1) Identification of molecular changes underlying the heart phenotype of Gpr126-/- mice.

2) Characterize cell type-specific deletion of Gpr126 in conditional Gpr126-/- mice.

3) Establishment of in vitro assays to analyze Gpr126 function and signaling.

4) Structure-function analysis of Gpr126 in zebrafish.

5) Defining binding partners of NTF-Gpr126

Publications

Musa G, Engel FB, Niaudet C (2016) Heart Development, Angiogenesis, and Blood-Brain Barrier Function Is Modulated by Adhesion GPCRs. Handbook of Experimental Pharmacology 234:351-368. 

Hamann J, Aust G, Arac D, Engel FB, Formstone C, Fredriksson R, Hall RA, Harty BL, Kirchhoff C, Knapp B, Krishnan A, Liebscher I, Lin H-H, Martinelli DC, Monk KR, Peeters MC, Piao X, Prömel S, Schöneberg T, Schwartz TW, Singer K, Stacey M, Ushkaryov YA, Vallon M, Wolfrum U, Wright MW, Xu L, Langenhan T, and Schiöth HB (2015) International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein-Coupled Receptors. Pharmacological Reviews 67:338–367.

Liebscher I, Ackley B, Araç D, Ariestanti DM, Aust G, Bae BI, Bista BR, Bridges JP, Duman JG, Engel FB, Giera S, Goffinet AM, Hall RA, Hamann J, Hartmann N, Lin HH, Liu M, Luo R, Mogha A, Monk KR, Peeters MC, Prömel S, Ressl S, Schiöth HB, Sigoillot SM, Song H, Talbot WS, Tall GG, White JP, Wolfrum U, Xu L, Piao X. New functions and signaling mechanisms for the class of adhesion G protein-coupled receptors. Ann N Y Acad Sci. 2014; 1333:43-64.

Patra C, Monk KR, Engel FB. The multiple signaling modalities of adhesion G protein-coupled receptor GPR126 in development. Receptor Clin Invest. 2014; 1:90-97.

Patra C, van Amerongen MJ, Ghosh S, Ricciardi F, Sajjad A, Novoyatleva T, Mogha A, Monk KR, Mühlfeld C, Engel FB. Organ-specific function of adhesion G protein-coupled receptor GPR126 is domain-dependent. Proc Natl Acad Sci U S A. 2013; 110(42):16898-903.

Mogha A, Benesh AE, Patra C, Engel FB, Schöneberg T, Liebscher I, Monk KR. Gpr126 functions in Schwann cells to control differentiation and myelination via G-protein activation. J Neurosci. 2013; 33(46):17986-94.

Araç D, Aust G, Calebiro D, Engel FB, Formstone C, Goffinet A, Hamann J, Kittel RJ, Liebscher I, Lin HH, Monk KR, Petrenko A, Piao X, Prömel S, Schiöth HB, Schwartz TW, Stacey M, Ushkaryov YA, Wobus M, Wolfrum U, Xu L, Langenhan T. Dissecting signaling and functions of adhesion G protein-coupled receptors. Ann N Y Acad Sci. 2012; 1276(1):1-25.