TY - JOUR
T1 - nNOS regulates ciliated cell polarity, ciliary beat frequency, and directional flow in mouse trachea
AU - Mikhailik, Anatoly
AU - Michurina, Tatyana V.
AU - Dikranian, Krikor
AU - Hearn, Stephen
AU - Maxakov, Vladimir I.
AU - Siller, Saul S.
AU - Takemaru, Ken Ichi
AU - Enikolopov, Grigori
AU - Peunova, Natalia
N1 - Funding Information:
We thank Ronald Crystal and Steven Gross (Cornell/Weill Medical College) for stimulating discussions and advice. We thank Julian Banerji for critical discussions and reading of the manuscript, Zach Glass and Kasim Sayed for their help with the experiments, Lisa Bianco and Gustavo Munoz for help with animals, Josh Z Huang (Cold Spring Harbor Laboratory) for the nNOS-CreER/Ai9 mouse trachea tissue, Tiansen Li (National Eye Institute) for rootletin antibody, and Guowei Tian for the help with two-photon Imaging. This work was supported by grants from the National Institute of Aging (R01AG AG057705) to G Enikolopov and N Peunova, from National Heart, Lung, and Blood Institute (5P20HL113443-02) to G Enikolopov and N Peunova, and intramural departmental grant to N Peunova.
Publisher Copyright:
© 2021 Mikhailik et al.
PY - 2021/3/2
Y1 - 2021/3/2
N2 - Clearance of the airway is dependent on directional mucus flow across the mucociliary epithelium, and deficient flow is implicated in a range of human disorders. Efficient flow relies on proper polarization of the multiciliated cells and sufficient ciliary beat frequency. We show that NO, produced by nNOS in the multiciliated cells of the mouse trachea, controls both the planar polarity and the ciliary beat frequency and is thereby necessary for the generation of the robust flow. The effect of nNOS on the polarity of ciliated cells relies on its interactions with the apical networks of actin and microtubules and involves RhoA activation. The action of nNOS on the beat frequency is mediated by guanylate cyclase; both NO donors and cGMP can augment fluid flow in the trachea and rescue the deficient flow in nNOS mutants. Our results link insufficient availability of NO in ciliated cells to defects in flow and ciliary activity and may thereby explain the low levels of exhaled NO in ciliopathies.
AB - Clearance of the airway is dependent on directional mucus flow across the mucociliary epithelium, and deficient flow is implicated in a range of human disorders. Efficient flow relies on proper polarization of the multiciliated cells and sufficient ciliary beat frequency. We show that NO, produced by nNOS in the multiciliated cells of the mouse trachea, controls both the planar polarity and the ciliary beat frequency and is thereby necessary for the generation of the robust flow. The effect of nNOS on the polarity of ciliated cells relies on its interactions with the apical networks of actin and microtubules and involves RhoA activation. The action of nNOS on the beat frequency is mediated by guanylate cyclase; both NO donors and cGMP can augment fluid flow in the trachea and rescue the deficient flow in nNOS mutants. Our results link insufficient availability of NO in ciliated cells to defects in flow and ciliary activity and may thereby explain the low levels of exhaled NO in ciliopathies.
UR - http://www.scopus.com/inward/record.url?scp=85102325117&partnerID=8YFLogxK
U2 - 10.26508/LSA.202000981
DO - 10.26508/LSA.202000981
M3 - Article
C2 - 33653689
AN - SCOPUS:85102325117
SN - 2575-1077
VL - 4
JO - Life Science Alliance
JF - Life Science Alliance
IS - 5
M1 - e202000981
ER -