Dr. Markus Ganter

markus.ganter
(at)med.uni-heidelberg.de
Phone: +49 6221 56–7877
Fax: +49 6221 56–5751

Nuclear Autonomy in Multinucleated Cells

Group Mem­bers

Projects

Cells usu­al­ly mul­ti­ply by dupli­cat­ing their genome and divide them­selves into two daugh­ter cells. Yet, in some organ­isms, cel­lu­lar mul­ti­pli­ca­tion fol­lows dis­tinct, some­what bizarre routes. One of these rather unusu­al ways can be seen in Plas­mod­i­um spp., the causative agent of malar­ia. An unusu­al fea­ture of Plas­mod­i­umrepli­ca­tion inside ery­thro­cytes, known as schizo­gony, is the num­ber of nuclei and, hence, daugh­ter cells they pro­duce dur­ing one round of intra­cel­lu­lar repli­ca­tion. Par­a­sites with odd num­bers of nuclei can be read­i­ly seen (Fig. 1). Diver­gence from a geo­met­ric expan­sion (e. 2, 4, 8, 16, or 32) is caused by asyn­chro­nous repli­ca­tion, sug­gest­ing that indi­vid­ual nuclei repli­cate autonomous­ly until a glob­al mech­a­nism takes over and co-ordi­nates daugh­ter cell for­ma­tion. This is in strik­ing con­trast with nuclear divi­sion in oth­er mult­i­n­u­cle­at­ed cells, such as the ear­ly Drosophi­la embryo, where nuclei fol­low a geo­met­ric expan­sion, as their divi­sion is rel­a­tive­ly syn­chro­nous. To gain insight into the reg­u­la­tion of Plas­mod­i­um fal­ci­parum repli­ca­tion, we con­duct­ed a for­ward genet­ic screen for the con­di­tion­al pro­tein expres­sion of pro­tein kinas­es and iden­ti­fied a kinase as essen­tial for pro­lif­er­a­tion (Fig. 2). This kinase is Plas­mod­i­um-spe­cif­ic and a cru­cial reg­u­la­tor of the con­tin­u­ous rounds of DNA repli­ca­tion, his­tone mod­i­fi­ca­tion, and reg­u­la­tion of gene expres­sion. We also found that this kinase is required for trans­mis­sion to the mos­qui­to. This work serves as a start­ing point to gain a bet­ter under­stand­ing of nuclear auton­o­my in Plas­mod­i­um.

Fig­ure 1 | Nuclei divide autonomous­ly in Plas­mod­i­um. Odd num­bers of nuclei can be read­i­ly seen dur­ing the devel­op­ment of P. fal­ci­parum.

Fig­ure 2 | Plas­mod­i­um fal­ci­parum CRK4 is essen­tial for repli­ca­tion in the path­o­gen­ic blood stage of infection.

1 | Analysis the spatiotemporal parameters of nuclear autonomy

To ana­lyze the spa­tiotem­po­ral para­me­ters of nuclear auton­o­my, we are using live-cell microscopy. In a set of reporter par­a­sites, we deter­mine the dynam­ics of DNA repli­ca­tion, nuclear divi­sion, and organelle devel­op­ment. These data inform on a math­e­mat­i­cal mod­el, describ­ing nuclear auton­o­my in P. fal­ci­parum (Fig. 3).

Fig­ure 3 | Plas­mod­i­um fal­ci­parum reporter cell line. The nuclei of the par­a­sites are marked with a red-flu­o­res­cent pro­tein and a com­po­nent of the DNA repli­ca­tion machin­ery (PCNA) is marked in cyan.

2 | Regulation of autonomous nuclei replication

To under­stand how autonomous nuclei reg­u­late their repli­ca­tion, we want to describe the sig­nalling cas­cade that orches­trates DNA repli­ca­tion in indi­vid­ual nuclei. For this we are using the may­or S‑phase reg­u­la­tor PfCRK4 as a start­ing point and are cur­rent­ly defin­ing its inter­ac­tome. This work will inform on sub­strates of the kinase as well as on upstream regulators.

Fig­ure 4 | Car­toon rep­re­sent­ing the elu­sive sig­nalling cas­cade, which trig­gers PfCRK4.

3 | Function of regulators and effectors in asynchromous DNA replication

Our pre­vi­ous work sug­gests that a set of pro­teins of unknown func­tion is involved in DNA repli­ca­tion and nuclear divi­sion. These pro­teins were iden­ti­fied through phos­pho­pro­teom­ic pro­fil­ing of PfCRK4 and showed a much-reduced phos­pho­ry­la­tion in absence of the kinase. To char­ac­ter­ize the func­tion of these reg­u­la­tors and effec­tors involved in asyn­chro­nous DNA repli­ca­tion, we are using reverse genet­ic tools and inducible gene-deple­tion approaches.

Fig­ure 5 | Change in phos­pho­ry­la­tion of three pro­teins of unknown func­tion in absence of CRK4. Phos­pho­pro­teom­ic pro­fil­ing of PfCRK4-deplet­ed par­a­sites. Grey areas indi­cate phos­pho­pep­tides with a ≥2‑fold change in phos­pho­ry­la­tion and p<0.05.

  • Weber S, Jeske R, Adeg­bite B, Glaser A, Moure P, Mouloun­gui-Mavoun­gou J, Rabone M, Emery A, Aka N, Jung H, Büch­ler C, Sorgho-Mitres­ka E, Tobian F, Plu­tows­ki-Wro­bel L, Gan­ter M, Lanz­er M, Vela­van T, Grobusch M, Denkinger C, Water­boer T, Adeg­ni­ka A, Bélard S. Clin­i­cal eval­u­a­tion of recom­bi­nant anti­gen ELISAs and broad-range helminth PCRs for the diag­no­sis of human parag­o­nimi­a­sis in Gabon (in press, Trop­i­cal Med­i­cine and Health).
  • Zink L, Reuschen­bach V, Sid Ahmed S, Lauer M, Nietham­mer J, Kudu­lyte A, Zorko K, Fack­ler OT, Hentzschel F, Gan­ter M. A genet­i­cal­ly encod­ed mark­er for imag­ing mem­branes of Plas­mod­i­um. Mol­e­c­u­lar Micro­bi­ol­o­gy, doi: 10.1111/mmi.70098, PMID: 42742062 (2026).
  • Binder P, Kudu­lyte A, Klaus S, Höfter T, Schwarz USS, †Gan­ter M, †Beck­er N. Com­pet­i­tive resource allo­ca­tion dri­ves asyn­chro­nous and rapid nuclear mul­ti­pli­ca­tion in the malar­ia par­a­site. Nature Com­mu­ni­ca­tions, 17, 7413, doi: 10.1038/s41467-026–75378‑x, PMID: 42509239 (2026).
  • Süt­ter­lin JM, Gan­ter M. Shap­ing an image: 3D-print­able mod­els of par­a­sites. Trends in Par­a­sitol­ogy, in press, doi: 10.1016/j.pt.2026.06.007 (2026)
  • Dey G, Gan­ter M, Jacobovitz M. Mult­i­n­u­cle­ation as a recur­ring evo­lu­tion­ary strat­e­gy for scal­ing and plas­tic­i­ty. Cur­rent Biol­o­gy, 36, R450–R463, doi: 10.1016/j.cub.2026.03.066, PMID: 42150533 (2026).
  • Malych R, Bor­dat Y, Klan­i­co­va K, Arbon D, Zahed­i­fard F, Sip­ko­va A, Drn­cová E, Levyt­s­ka V, Mach J, Plu­tows­ki-Wro­bel L, Macha­do M, Stur­sa J, Truk­sa J, Gan­ter M, Soj­ka D, Zolt­ner M, Besteiro S, Wern­er L, Sutak R. Mod­u­lar Design of Mito­chon­dri­on-Tar­get­ed Iron Chela­tors Allows High­ly Selec­tive Antipar­a­sitic Activ­i­ty against Try­panosomes and Api­com­plex­an Par­a­sites. ACS Infec­tious Dis­eases, doi: 10.1021/acsinfecdis.5c00548, PMID: 41428959 (2025).
  • Nikolo­va V, Lin­ne­mannstoens K, Ben­del M‑E, Macha­do M, Gan­ter B, Budimir P, Vogts M, Gan­ter M, Meier C, Dobbel­stein M. Mem­brane-per­me­able 5‑fluorodeoxyuridine triphos­phate deriv­a­tives inhib­it the pro­lif­er­a­tion of Plas­mod­i­um fal­ci­parum. ACS Infec­tious Dis­eases, doi.org/10.1021/acsinfecdis.5c00544, PMID: 41042506 (2025).
  • Nikolo­va V, Lin­ne­mannstoens K, Zaho­ruiko A, Gan­ter M, Lued­er CG, Dobbel­stein M. Syn­er­gis­tic activ­i­ty of the fer­rop­to­sis induc­er RSL3 and Pyrimethamine to inhib­it the pro­lif­er­a­tion of Plas­mod­i­um fal­ci­parum. Antimi­cro­bial Agents and Chemother­a­py, e0047125, PMID: 40823867 (2025)
  • Dupouy B, Cotos-Munoz L, Binder A, Borko­va L, Rottmann M, Mäs­er P, Jacquemin D, Gan­ter M, Davi­oud-Charvet E, Elhabiri M. Click Cou­pling of Flavyli­um Dyes with Plas­modi­one Ana­logues: Towards New Redox-Sen­si­tive Pro-Flu­o­rophores. Chem­istry — A Euro­pean Jour­nal, 31, e202403691, PMID:39654502 (2025)
  • Darif N‑D, Gan­ter M, Dziekan JM, Kil­ian N, Bran­cuc­ci N, Ng C, de Vries LE, Gut­tery D, Philip N, Boddey JA, Met­wal­ly NG, Oku­mu F, Kooij TWA, Absa­lon S, Bryant JM. Bio­Ma­l­Par XX: look­ing back on, and for­ward from, 20 years of malar­ia research. Trends in Par­a­sitol­ogy, doi.org/10.1016/j.pt.2024.06.012, PMID: 39013661 (2024)
  • Arbon D, Mach J, Sip­ko­va A, Štur­sa J, Klan­i­co­va K, Macha­do M, Gan­ter M, Levyt­s­ka V, Soj­ka D, Truk­sa J, Wern­er L, Sutak R. Chela­tion of mito­chon­dr­i­al iron as an antipar­a­sitic strat­e­gy. ACS Infec­tious Dis­eases, 10, 676–687, PMID: 38287902 (2024)
  • Voß Y, Klaus M, Nico­las P. Lichti, Gan­ter M, Guizetti J. Malar­ia par­a­site cen­trins assem­ble by Ca2+-inducible con­den­sa­tion. Plos Pathogens, 19, e1011899, PMID: 38150475 (2023)
  • Macha­do M, Klaus S, Klasch­ka D, Guizetti J, Gan­ter M. Plas­mod­i­um fal­ci­parum CRK4 links ear­ly mitot­ic events to the onset of S‑phase dur­ing schizo­gony. mBio, e0077923, PMID: 37345936 (2023)
  • Wenz C, Simon CS, Romão TP, Stürmer V, Macha­do M, Klages N, Klem­mer A, Voß Y, Gan­ter M, Bro­chet M, Guizetti J. An Sfi1-like cen­trin-inter­act­ing cen­tri­o­lar plaque pro­tein affects nuclear micro­tubule home­osta­sis. Plos Pathogens, 19, e1011325, PMID: 37130129 (2023)
  • Voß Y, Klaus S, Guizetti J, Gan­ter M. Plas­mod­i­um schizo­gony, a chronol­o­gy of the parasite’s cell cycle in the blood stage. Plos Pathogens, 19, e1011157, PMID: 36862652 (2023)
  • Gan­ter M, Guizetti J, Kil­ian N. Visu­al­iza­tion of Infect­ed Red Blood Cell Sur­face Anti­gens by Flu­o­res­cence Microscopy. In Malar­ia Immunol­o­gy, Tar­get­ing the Sur­face of Infect­ed Ery­thro­cytes, edit­ed by Ram­st­edt Jensen AT, Hvi­id L. Meth­ods in Mol­e­c­u­lar Biol­o­gy, 2470:425–433, PMID: 35881363 (2022)
  • Arbon D, Ženíšková K, Šubr­tová K, Mach J, Štur­sa J, Macha­do M, Zahed­i­fard F, Lešti­nová T, Hier­ro Yap C, Neuzil J, Volf P, Gan­ter M, Zolt­ner M, Zíková A, Wern­er L, Sutak R. Repur­pos­ing of mito­chon­dria-tar­get­ed tamox­ifen: Nov­el anti-can­cer drug exhibits potent activ­i­ty against major pro­to­zoan and fun­gal pathogens. Antimi­cro­bial Agents and Chemother­a­py, e00727-22, PMID: 35856666 (2022)
  • Klaus S, Binder P, Kim J, Macha­do M, Funaya C, Schaaf V, Klasch­ka D, Kudu­lyte A, Cyrk­laff M, Lake­ta V, Hoe­fer T, Guizetti J, Beck­er N, Frischknecht F, Schwarz US, Gan­ter M. Asyn­chro­nous nuclear cycles in mult­i­n­u­cle­at­ed Plas­mod­i­um fal­ci­parum enable rapid pro­lif­er­a­tion. Sci­ence Advances, 8(13):eabj5362, PMID: 35353560 (2022)
    • *This paper was the sub­ject of a Trends in Par­a­sitol­ogy Spot­light, Liffn­er, B. & Absa­lon, S. 2022. Hand-in-hand advances in microscopy and Plas­mod­i­um nuclear biol­o­gy. Trends in Par­a­sitol­ogy, 38:421–423
    • #The cor­re­spond­ing preprint was the sub­ject of a pre­Light arti­cle by João Mel­lo-Vieira (05/2021), doi.org/10.1242/prelights.29113
  • Van­dor­pe DH, Rivera A, Gan­ter M, Dankwa S, Wohlge­muth J, Dlott J, Sny­der LM, Brug­nara C, Durais­ingh MT, Alper SL. Puriner­gic sig­nal­ing is essen­tial for full Psick­le acti­va­tion by hypox­ia and by nor­mox­ic acid pH in mature human sick­le red cells and in vit­ro-dif­fer­en­ti­at­ed cul­tured human sick­le retic­u­lo­cytes. Pflügers Archiv — Euro­pean Jour­nal of Phys­i­ol­o­gy, 474(5):553–565, PMID: 35169901 (2022)
  • Schu­mann R, Bischoff E, Klaus S, Möhring S, Flock J, Keller S, Remans K, Gan­ter M, Deponte M. Pro­tein abun­dance and fold­ing rather than the redox state of Kelch13 deter­mine the artemisinin sus­cep­ti­bil­i­ty of Plas­mod­i­um fal­ci­parum. Redox Biol­o­gy, 48: 102177, PMID: 34773836 (2021)
  • Simon CS, Voss Y, Funaya C, Macha­do M, Pen­ning A, Klasch­ka D, Cyrk­laff M, Kim J, Gan­ter M, Guizetti J. An extend­ed DNA-free intranu­clear com­part­ment orga­nizes cen­tro­so­mal micro­tubules in malar­ia par­a­sites. Life Sci­ence Alliance, 4: e202101199, PMID: 34535568 (2021)
    • *This paper was the sub­ject of a Trends in Par­a­sitol­ogy Spot­light, Liffn­er, B. & Absa­lon, S. 2022. Hand-in-hand advances in microscopy and Plas­mod­i­um nuclear biol­o­gy. Trends in Par­a­sitol­ogy, 38:421–423
  • Gan­ter M and Frischknecht F. Illu­mi­nat­ing Plas­mod­i­um inva­sion by lat­tice light sheet microscopy. Trends in Par­a­sitol­ogy, 37:777–779 PMID: 34332896 (2021)
  • Macha­do M, Steinke S, Gan­ter M. Plas­mod­i­um Repro­duc­tion, Cell Size, and Tran­scrip­tion: How to cope with increas­ing DNA con­tent? Fron­tiers in Cell Infec­tion Micro­bi­ol­o­gy, 11, 660679, PMID: 33898332 (2021)
  • Pape C, Remme R, Wol­ny A, Olberg S, Wolf S, Cer­rone L, Cortese M, Klaus S, Lucic B, Ull­rich S, Anders-Öss­wein M, Wolf S, Berati C, Neufeld C, Gan­ter M, Schnit­zler P, Mer­le U, Lusic M, Boulant S, Stan­i­fer M, Barten­schlager R, Ham­precht FA, Kreshuk A, Tis­ch­er C, Kräus­slich H‑G, Müller B and Lake­ta V. Microscopy-based assay for semi-quan­ti­ta­tive detec­tion of SARS-CoV­‑2 spe­cif­ic anti­bod­ies in human sera. BioEs­says, 2000257, PMID: 33377226 (2021)
  • Quadt K, Smyr­nakou X, Frischknecht F, Böse G, Gan­ter M. Plas­mod­i­um fal­ci­parum par­a­sites exit the infect­ed ery­thro­cyte after haemol­y­sis with saponin and strep­tolysin O. Par­a­sitol­ogy Research, 119:4297–4302, PMID: 33089360 (2020)
  • Przy­bors­ki J and Gan­ter M. Das ungewöhn­liche Leben der Malar­i­a­par­a­siten. Biolo­gie in Unser­er Zeit, 48,162–169; doi.org/10.1002/biuz.201810646 (2018)
  • Gan­ter M, Gold­berg JM, Dvorin JD, Paulo JA, King JG, Tri­pathi AK, Paul AS, Yang J, Cop­pens I, Jiang RHY, Elsworth B, Bak­er DA, Din­glasan RR, Gygi SP, Durais­ingh MT. Plas­mod­i­um fal­ci­parum CRK4 directs con­tin­u­ous rounds of DNA repli­ca­tion dur­ing schizo­gony. Nature Micro­bi­ol­o­gy, 2(5):17017, PMID: 28211852 (2017)
  • Paul AS, Saha S, Engel­berg K, Jiang RHY, Cole­man BI, Kos­ber AL, Chen C, Gan­ter M, Espy N, Gilberg­er TW, Gubbels MJ, Durais­ingh MT. Par­a­site cal­cineurin reg­u­lates host cell recog­ni­tion and attach­ment by api­com­plex­ans. Cell Host Microbe, 18:49–60, PMID: 26118996 (2015)
  • Gan­ter M, Rizopou­los Z, Schuler H, Matuschews­ki K. Piv­otal and dis­tinct role for Plas­mod­i­um actin cap­ping pro­tein alpha dur­ing blood infec­tion of the Malar­ia par­a­site. Mol­e­c­u­lar Micro­bi­ol­o­gy, 96:84–94, PMID: 25565321 (2015)
  • Cole­man BI, Skill­man KM, Jiang RHY, Childs LM, Altenhofen LM, Gan­ter M, Leung Y, Goldowitz I, Kaf­sack BFC, Mar­ti M, Lli­nas M, Buc­k­ee CO, Durais­ingh MT. A Plas­mod­i­um fal­ci­parum his­tone deacety­lase reg­u­lates anti­genic vari­a­tion and game­to­cyte con­ver­sion. Cell Host Microbe, 16:177–186, PMID: 25121747 (2014)
  • Sat­tler J, Gan­ter M, Hliscs M, Matuschews­ki K, Schuler H. Actin reg­u­la­tion in the malar­ia par­a­site. Euro­pean Jour­nal of Cell Biol­o­gy, 90:966–971, PMID: 21256619 (2011)
  • Siden-Kiamos I, Gan­ter M, Kun­ze A, Hliscs M, Stein­büchel M, Men­doza J, Sin­den R, Louis K, Matuschews­ki K. Stage-spe­cif­ic deple­tion of myosin A sup­ports an essen­tial role in motil­i­ty of malar­i­al ookinetes. Cel­lu­lar Micro­bi­ol­o­gy, 13(12):1996–2006, PMID: 21899701 (2011)
  • Gan­ter M, Schuler H, Matuschwes­ki K. Vital role for the Plas­mod­i­um cap­ping pro­tein (CP) beta sub­unit in motil­i­ty of malar­ia sporo­zoites. Mol­e­c­u­lar Micro­bi­ol­o­gy, 74:1356–1367, PMID: 19682250 (2009)
  • Kur­su­la I, Kur­su­la P, Gan­ter M, Pan­jikar S, Matuschews­ki K, Schuler H. Struc­tur­al basis for par­a­site-spe­cif­ic func­tions of the diver­gent pro­fil­in of Plas­mod­i­um fal­ci­parum. Struc­ture, 16:1638–1648, PMID: 19000816 (2008)

  • US 11,796,542 B2 / WO2018002327A1 (pub­lished Jan­u­ary 4th 2018), Rapid Test for the Detect­ing Pathogens and Cells and Method, Zen­dia GmbH, Inven­tor: Böse G, Gan­ter M, Rajabi T, Guber A, Ahrens R.