Asymmetrically Positioned Flagellar Control Units Regulate Human Sperm Rotation

Miller, Melissa R.; Kenny, Samuel J.; Mannowetz, Nadja; Mansell, Steven A.; Wojcik, Michal; Mendoza, Sarah; Zucker, Robert S.; Xu, Ke; Lishko, Polina V.

doi:10.2139/ssrn.3188435

Cited by 7 publications

(20 citation statements)

References 55 publications

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“…5E), in contrast with the circular arcs in Chlamydomonas mutants (29). Our observations are consistent with reports showing a hierarchy of distinct asymmetries in flagellar systems, from asymmetric distribution and activity of molecular motors (25,31,32) to asymmetric bending in hamster spermatozoa (37), asymmetric static modes in Chlamydomonas (23,27), atypical centriole (33), and an ever growing number of asymmetric regulatory complexes (10,27,29,34,35) in addition to other unknown biases from less well-studied motor proteins (36). While the exact molecular mechanism underlying the observed asymmetric static shape is still unknown (23,27), our results show that, together with murine spermatozoa (37) and Chlamydomonas flagellum (23), the human sperm flagellum is part of the asymmetric beating-flagellated microorganisms that exhibit an intrinsically asymmetric static mode, reflecting potential universal asymmetries across species.…”

Section: Molecular and Structural Origin Of Beating Asymmetry And Anisupporting

confidence: 91%

“…The postulation of symmetric beating is, however, in contrast with the abundance of observations showing structural asymmetries within the flagellar scaffold (2,10,20,23,(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36). Asymmetric waves have been reported in murine spermatozoa (37,38), while a one-sided stroke is commonly observed in Chlamydomonas (23,(27)(28)(29).…”

Section: Introductionmentioning

confidence: 90%

“…Asymmetric waves have been reported in murine spermatozoa (37,38), while a one-sided stroke is commonly observed in Chlamydomonas (23,(27)(28)(29). Ultrastructural anisotropies and asymmetries are intrinsic to mammalian sperm (2,20,30), present at every level, from asymmetric dynein activity (25,26,31,32) to atypical centriole (33) and an ever growing number of regulatory complexes (10,27,29,(34)(35)(36), including anisotropic localization of membrane ion channels, which are criti-cal for sperm capacitation (10,34). These intrinsic molecular asymmetries must somehow still dictate the flagellar coordination and be manifested in the flagellar beat itself.…”

Section: Introductionmentioning

confidence: 99%

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Human sperm uses asymmetric and anisotropic flagellar controls to regulate swimming symmetry and cell steering

et al. 2020

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Flagellar beating drives sperm through the female reproductive tract and is vital for reproduction. Flagellar waves are generated by thousands of asymmetric molecular components; yet, paradoxically, forward swimming arises via symmetric side-to-side flagellar movement. This led to the preponderance of symmetric flagellar control hypotheses. However, molecular asymmetries must still dictate the flagellum and be manifested in the beat. Here, we reconcile molecular and microscopic observations, reconnecting structure to function, by showing that human sperm uses asymmetric and anisotropic controls to swim. High-speed three-dimensional (3D) microscopy revealed two coactive transversal controls: An asymmetric traveling wave creates a one-sided stroke, and a pulsating standing wave rotates the sperm to move equally on all sides. Symmetry is thus achieved through asymmetry, creating the optical illusion of bilateral symmetry in 2D microscopy. This shows that the sperm flagellum is asymmetrically controlled and anisotropically regularized by fast-signal transduction. This enables the sperm to swim forward.

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Section: Molecular and Structural Origin Of Beating Asymmetry And Anisupporting

confidence: 91%

Section: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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Human sperm uses asymmetric and anisotropic flagellar controls to regulate swimming symmetry and cell steering

et al. 2020

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“…In this regard, it was recently reported the asymmetrically distribution of Hv1 channel in the human sperm flagellum, which is responsible, at least in part, for the increase in pHi (Lishko et al, 2010). This specific localization of Hv1 could produce local alkalization when positioned in close proximity to a subset of CatSper channels resulting in asymmetric local Ca 2+ changes that may be required for the complex movement of the sperm flagellum (Miller et al, 2018). In mouse, the alkalinization of the cytoplasm during capacitation occurs as a result of Na + -H + exchangers (NHE) (Chávez et al, 2014;Wang et al, 2003;Wang et al, 2007) since there is no clear evidence showing a significant role of Hv1 channels.…”

Section: Discussionmentioning

confidence: 98%

“…This segregated localization of proteins in the tail may provide the structural basis for the selective activation of CatSper and the normal development of hyperactivated motility. For example, recent superresolution microscopy experiments in human sperm revealed that Hv1, the voltagegated proton channel involved in cytoplasmic alkalinization, is distributed asymmetrically within bilateral longitudinal lines and that inhibition of this channel leads to a decrease in sperm rotation along the long axis (Miller et al, 2018). In addition, other signaling molecules such as Caveolin-1, phosphorylated Ca 2+ /calmodulindependent protein kinase II (P-CaMKII), calcineurin (PPP3C aka PP2B) and EFCAB9 colocalize with CatSper displaying a similar spatial distribution along the principal piece in mouse sperm (Chung et al, 2014;Hwang et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Cdc42 activity is essential for the interplay between cAMP/PKA pathway and CatSper function

Luque

Romarowski

et al. 2020

Preprint

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Sperm acquire the ability to fertilize in a process called capacitation and undergo hyperactivation, a change in the motility pattern, which depends on Ca2+ transport by CatSper channels. CatSper is essential for fertilization and it is subjected to a complex regulation that is not fully understood. Here, we report that similar to CatSper, Cdc42 distribution in the principal piece is confined to four linear domains and this localization is disrupted in CatSper1-null sperm. Cdc42 inhibition impaired CatSper activity and other Ca2+-dependent downstream events resulting in a severe compromise of the sperm fertilizing potential. We also demonstrate that Cdc42 is essential for CatSper function by modulating cAMP production by sAC, providing a new regulatory mechanism for the stimulation of CatSper by the cAMP/PKA-dependent pathway. These results reveal a broad mechanistic insight into the regulation of Ca2+ in mammalian sperm, a matter of critical importance in male infertility as well as in contraception.

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Human sperm ion channel (dys)function: implications for fertilization

Brown

Publicover

Barratt

et al. 2019

Human Reproduction Update

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BACKGROUNDIntensive research on sperm ion channels has identified members of several ion channel families in both mouse and human sperm. Gene knock-out studies have unequivocally demonstrated the importance of the calcium and potassium conductances in sperm for fertility. In both species, the calcium current is carried by the highly complex cation channel of sperm (CatSper). In mouse sperm, the potassium current has been conclusively shown to be carried by a channel consisting of the pore forming subunit SLO3 and auxiliary subunit leucine-rich repeat-containing 52 (LRRC52). However, in human sperm it is controversial whether the pore forming subunit of the channel is composed of SLO3 and/or SLO1. Deciphering the role of the proton-specific Hv1 channel is more challenging as it is only expressed in human sperm. However, definitive evidence for a role in, and importance for, human fertility can only be determined through studies using clinical samples.OBJECTIVE AND RATIONALEThis review aims to provide insight into the role of sperm ion channels in human fertilization as evidenced from recent studies of sperm from infertile men. We also summarize the key discoveries from mouse ion channel knock-out models and contrast the properties of mouse and human CatSper and potassium currents. We detail the evidence for, and consequences of, defective ion channels in human sperm and discuss hypotheses to explain how defects arise and why affected sperm have impaired fertilization potential.SEARCH METHODSRelevant studies were identified using PubMed and were limited to ion channels that have been characterized in mouse and human sperm. Additional notable examples from other species are included as appropriate.OUTCOMESThere are now well-documented fundamental differences between the properties of CatSper and potassium channel currents in mouse and human sperm. However, in both species, sperm lacking either channel cannot fertilize in vivo and CatSper-null sperm also fail to fertilize at IVF. Sperm-lacking potassium currents are capable of fertilizing at IVF, albeit at a much lower rate. However, additional complex and heterogeneous ion channel dysfunction has been reported in sperm from infertile men, the causes of which are unknown. Similarly, the nature of the functional impairment of affected patient sperm remains elusive. There are no reports of studies of Hv1 in human sperm from infertile men.WIDER IMPLICATIONSRecent studies using sperm from infertile men have given new insight and critical evidence supporting the supposition that calcium and potassium conductances are essential for human fertility. However, it should be highlighted that many fundamental questions remain regarding the nature of molecular and functional defects in sperm with dysfunctional ion channels. The development and application of advanced technologies remains a necessity to progress basic and clinical research in this area, with the aim of providing effective screening methodologies to identify and develop treatments for affected men in order t...

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Asymmetrically Positioned Flagellar Control Units Regulate Human Sperm Rotation

Cited by 7 publications

References 55 publications

Human sperm uses asymmetric and anisotropic flagellar controls to regulate swimming symmetry and cell steering

Human sperm uses asymmetric and anisotropic flagellar controls to regulate swimming symmetry and cell steering

Cdc42 activity is essential for the interplay between cAMP/PKA pathway and CatSper function

Human sperm ion channel (dys)function: implications for fertilization

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