The actin nucleator Cordon-Bleu (Cobl) - elucidation of regulatory mechanisms and cellular function - II
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
Actin filament polymerization is essential for processes as diverse as cell morphology control, the formation of multicellular networks, cell migration and membrane trafficking processes. Indispensable is thereby a tight spatial and temporal control of actin filament nucleation. With the multiple WH2 domain-containing protein Cobl, we have identified a novel and very powerful actin nucleator. Our studies have unraveled that Cobl plays an important role in proper formation of neuronal cell morphology - a prerequisite for the formation of functional neuronal networks. Analyses on the tissue and organism level now aimed at revealing the structural and functional pathophysiological consequences upon Cobl deficiency in vivo. The successful establishment of Cobl-deficient organisms has successfully provided insights into the role of this new actin nucleator in cellular development, differentiation and function in the intact organism. Strikingly, among other phenotypes, these studies also showed that different types of ciliary structures rely on the function of the actin nucleator Cobl. Proper cochlear hair cell array development and sensory apparatus positioning are achieved by planar cell polarity signaling. Effectors executing proper tissue development and maturation programs are largely unknown. Our analyses showed that the actin nucleator Cobl is an important effector in postnatal refinement and maintenance of planar cell polarity. During the critical time of hearing onset, these polarity defects caused by Cobl KO coincided with reduced F-actin beneath the sensory apparatus and with premature kinocilium retraction. These defects were accompanied by organizational defects of the pericentriolar scaffold that coincided with basal body and centriolar mispositionings. Importantly, the pericentriolar defects observed in Cobl KO mice were demonstrated to be actin polymerization-dependent and calcium/calmodulin signaling-dependent and thereby clearly reflect our insights into the molecular mechanisms of Cobl’s function, as Cobl is an actin nucleator and is controlled by calcium/calmodulin signaling. Because we observed that Cobl KO phenotypes manifested postnatally, we were able to firmly concluded that surprisingly planar cell polarity formation is not solely an important developmental process. The Cobl-dependent planar cell polarity maintenance and refinement processes we discovered seem critical for hearing, as Cobl KO mice show deficient cochlear amplification. Our successfully executed analyses of the consequences of a loss of Cobl at the cellular, tissue and organism level significantly expanded our molecular understanding of the functions of the cortical actin cytoskeleton - functions that are indispensable for live of all higher eukaryots.
Publications
- (2011). The functions of the actin nucleator Cobl in cellular morphogenesis critically depend on syndapin I. EMBO J. 30, 3147-3159
Schwintzer L, Koch N, Ahuja R, Grimm J, Kessels MM, Qualmann B
(See online at https://doi.org/10.1038/emboj.2011.207) - (2012). Abp1 utilizes the Arp2/3 complex activator Scar/WAVE in bristle development. J. Cell Sci. 125, 3578-3589
Koch N, Dharmalingam E, Westermann M, Qualmann B, Thomas U, Kessels MM
(See online at https://doi.org/10.1242/jcs.101451) - (2012). The actin nucleator Cobl is crucial for Purkinje cell development and works in close conjunction with the F-actin binding protein Abp1. J. Neurosci. 32, 17842-17856
Haag N, Schwintzer L, Ahuja R, Koch N, Grimm J, Heuer H, Qualmann B, Kessels MM
(See online at https://doi.org/10.1523/JNEUROSCI.0843-12.2012) - (2013). Ciliated sensory hair cell formation and function require the F-BAR protein syndapin I and the WH2 domain-based actin nucleator Cobl. J. Cell Sci 126, 196-208
Schüler S, Hauptmann J, Perner B, Kessels MM, Englert C, Qualmann B
(See online at https://doi.org/10.1242/jcs.111674) - (2014). Terminal axonal arborization and synaptic bouton formation critically rely on Abp1 and the Arp2/3 complex. PLoS One 9, e97692
Koch N, Kobler O, Thomas U, Qualmann B, Kessels MM
(See online at https://doi.org/10.1371/journal.pone.0097692) - (2015). The actin nucleator Cobl is controlled by calcium and calmodulin. PLoS Biol. 13, e1002233
Hou W, Izadi M, Nemitz S, Haag N, Kessels MM, Qualmann B
(See online at https://doi.org/10.1371/journal.pbio.1002233) - (2018). Arginine methylation by PRMT2 controls the functions of the actin nucleator Cobl. Dev. Cell 45, 262-275
Hou W, Nemitz S, Schopper S, Nielsen ML, Kessels MM, Qualmann B
(See online at https://doi.org/10.1016/j.devcel.2018.03.007) - (2018). Cobl-like promotes actin filament formation and dendritic branching using only a single WH2 domain. J. Cell Biol. 217, 211-230
Izadi M, Schlobinski D, Lahr M, Schwintzer L, Qualmann B, Kessels MM
(See online at https://doi.org/10.1083/jcb.201704071) - (2018). Direct effects of Ca2+/calmodulin on actin filament formation. Biochem. Biophys. Res. Commun. 506, 355-360
Izadi M, Hou W, Qualmann B, Kessels MM
(See online at https://doi.org/10.1016/j.bbrc.2018.07.159) - (2018). The actin nucleator Cobl is critical for centriolar positioning, postnatal planar cell polarity refinement, and function of the cochlea. Cell Rep. 24, 2418-2431
Haag N, Schüler S, Nietzsche S, Hübner CA, Strenzke N, Qualmann B, Kessels MM
(See online at https://doi.org/10.1016/j.celrep.2018.07.087)
