Integration of scRNAseq data and Notch code from micropatterns will generate in-depth insight into how JAG1 mutation impacts on specific cell populations and developmental processes to resultsyndrome

OTHER FUNDING

REFERENCES

1 INTRODUCTION

EXPERIENCE

3 PROJECT SUMMARY

4

6 HIRING

Alagille syndrome (ALGS)1,2 is a rare (1:30-70 000) hereditarydevelopmental disorder with multi-systemic phenotypicmanifestation presenting defects in liver, heart, vasculature,skeleton, and kidneys, reviewed in3. ALGS is caused bymutations in Notch signaling components JAG1 (~94% ofcases)4,5 or NOTCH2 (~2%)6. Notably, several reports alsodescribe an increased incidence of infections in patientswith ALGS (25-35% of cases), further complicating diseasetreatment7,8.JAG1 signaling has been implicated in the regulation ofhaematopoiesis9–12 and immune cell maturation in bothmouse13 and human14. Since embryonic hepatichaematopoiesis precedes liver metabolic function 15,16, andsince Jag1-/- mice die early in embryogenesis (E10.5)17, due tovascular defects, we used a JAG1 (H268Q) missense carryingJag1Ndr/Ndr mouse model, faithfully recapitulating ALGS18, toaddress the function of Jag1 and other Notch components inhaematopoiesis in Alagille syndrome.

1. Alagille, D., Odièvre, M., Gautier, M. & Dommergues, J. P. P. J. Pediatr. 86, 63–71 (1975).2. Watson, G. H. & Miller, V. Arch. Dis. Child. 48, 459–66 (1973).3. Mašek, J. & Andersson, E. R. Development 144, 1743–1763 (2017).4. Li, L. et al. Nat Genet 16, 243–51. (1997).5. Oda, T. et al. Nat. Genet. 16, 235–242 (1997).6. McDaniell, R. et al. Am. J. Hum. Genet. 79, 169–73 (2006).7. Tilib Shamoun, S., Le Friec, G., Spinner, N., Kemper, C. & Baker, A. J. Clin. Res. Hepatol. Gastroenterol.

39, 566–569 (2015).8. Quiros-Tejeira, R. E. et al. J. Pediatr. Gastroenterol. Nutr. 29, 431–437 (1999).9. Robert-Moreno, À. et al. EMBO J. 27, 1886–1895 (2008).

10. Varnum-Finney, B. et al. Blood 91, 4084–4091 (1998).11. Karanu, F. N. et al. J. Exp. Med. 192, 1365–1372 (2000).12. Poulos, M. G. et al. Cell Rep. 4, 1022–1034 (2013).13. Cahill, E. F., Tobin, L. M., Carty, F., Mahon, B. P. & English, K. Stem Cell Res. Ther. 6, 19 (2015).14. Weijzen, S. et al. J. Immunol. 169, 4273–4278 (2002).15. Popescu, D. M. et al. Nature 574, 365–371 (2019).16. Nakagaki, B. N. et al. J. Hepatol. 69, 1294–1307 (2018).17. Xue, Y. et al. Hum. Mol. Genet. 8, 723–730 (1999).18. Andersson, E. R. et al. Gastroenterology (2017) doi:10.1053/j.gastro.2017.11.002.

Jan MAŠEK1, Emma R. ANDERSSON Lab

1 Karolinska Institute, Stockholm, Sweden

Cracking the notch code in Alagille syndrome: single-cell receptor-

ligand interactions and outcomes in vivo

8 CONTACTJan Mašek | PhDjan.masek@ki.se |anderssonlab.commasekj86@gmail.com | Masek_lab

7

Wenner-Gren Stiftelserna

Mašek and Andersson, 2017 (1)

ALGSImmunodeficiency?

Please visit poster #286 (Friday) to learn more

about the role of Jagged1 in physiological hepatic hematopoiesis and its potential contribution to ALGS pathology.

Alagille syndrome

Single-cell RNAseq of the mouse developing liver to identify Notch-active cell populations

Notch Code

High throughput imaging of Notch reporter activity, on micropatterns, in CRISPR Notch-null cells over-

expressing tagged receptors and ligands

5 NEW BEGINNING

POSTDOC - full salary covered 3 years

PHDs - combination of 50% stipend and 50% salary covered for 4 years

Start : form 4/2021

Applicants please send your CV, motivation and a reference letters using subject name: ”MASEKLAB APPLICATION 2020”.

WHAT RESEARCH? - Medically relevant basic research focusing on Non-canonical Notch signaling and WNT/NOTCH crosstalks in development, homeostais and disease.

WHERE? - Prague, Czech Republic

WHEN? - Lab is starting 4/2021

2

How does abrogated JAG1 impact on specific Notch receptor-ligand interactions, and result in the complex disease presentation that is Alagille syndrome?

to resolve the signaling output of specific receptor/ligand combinations

Integration of scRNAseq data and Notch code from micropatterns will generate in-depth insight into how JAG1 mutation impacts on specific cell populations and developmental processes to result in Alagille syndrome.