Abstract
The functional properties of mucosal surfaces are dependent on establishing the correct proportions of specialized epithelial cell types. Multiciliated cells (also known as ciliated cells) are evolutionarily conserved and functionally indispensable epithelial cells, as suggested by the link between ciliated cell dysfunction and chronic human disease. Ciliated cell differentiation is an ordered process that involves initial cell fate determination and multiciliogenesis. STK11, a serine/threonine kinase, has been reported to be downregulated in human diseases associated with ciliopathies and functions as a tumor suppressor. Here, we show that STK11 is a physiological factor for the normal program of ciliated cell differentiation by phosphorylating MARK3, which directly suppresses ERK1/2 mediated pRB inactivation. Loss of Stk11 in airway progenitors impairs the differentiation of ciliated cells in both embryonic and adult airways. Our study establishes that STK11/MARK3/ERK1/2 signaling cascade is a key regulator to integrate ciliated cell fate commitment and the subsequent process of multiciliogenesis.
Highlights
The airway epithelium serves critical functions to protect the lung from environmental insults
We investigated downstream phosphorylation targets of STK1139. qPCR analysis showed that two of 13 targets are expressed at substantial levels in the airway epithelium of E16.5 lungs: protein kinase AMP-activated catalytic alpha[1] subunit (PRKAA1, known as AMPKα1) and microtubule affinity-regulating kinase 3 (MARK3) (Fig. 5a, Supplementary Fig. S5a, b)
Scale bars: 11 μm for their activation (Fig. 5a, Supplementary Fig. S5b). Both in vivo and in vitro, that adenosine monophosphate 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of PRKAA142,43, had no impact on either the proliferative status of airway epithelial cells or ciliated cell differentiation (Supplementary Fig. S5c–l); we there subsequently focused on roles for MARK3 as a downstream mediator of STK11
Summary
The airway epithelium serves critical functions to protect the lung from environmental insults. It is known that the balance between secretory and ciliated cells is fundamental for normal airway function. Impaired differentiation or abnormal functions of secretory and/or ciliated cells lead to many respiratory diseases, including airway infections, cystic fibrosis lung disease, and chronic obstruction pulmonary disease[1]. Ciliated cells are derived from multipotent endodermal progenitor cells of the embryonic lung and either secretory or basal progenitors of the postnatal airway[2]. Seminal work has demonstrated that Notch signaling, an evolutionarily conserved cell fate determinant, plays a key role in controlling the balance between secretory versus ciliated cell fates in both embryonic and adult lungs[3,4,5,6,7,8,9,10]
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