# Amelogenesis and Ion Transport

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2021 · $352,688

## Abstract

PROJECT SUMMARY / ABSTRACT
During enamel formation (amelogenesis) the regulation of extracellular pH (pHe) is critical as shown by
multiple mutant mice lines. Bicarbonate (HCO3-) export to the enamel matrix involves anion exchanger 2 (AE2)
and members of the SLC26A gene family. AE2 is localized to the lateral membrane of maturation ameloblasts,
while SLC26A1, 3, 4, 6 and 7 all localize to the apical/distal membrane of these same cells. In maturation
ameloblasts SLC26A proteins colocalize with the cystic fibrosis transmembrane conductance regulator
(CFTR) and function together to allow for the export of HCO3- and the bidirectional movements of chloride ions
(Cl-) as part of the pHe regulatory process. In other polarized epithelial cell types of a secretory nature,
SLC26A proteins and CFTR form a network with cytoskeletal filamentous actin (F-actin) at the apical pole
dictating, to a large part, cell polarity and microvilli projections. NHERF1/SLC9A3R1 and Ezrin proteins are
also involved with this network interaction. The pH-sensitive sodium dependent phosphate transporter
(SLC34A2/NaPi2b), an inorganic phosphate (Pi) import channel also localizes to the apical pole of maturation
ameloblasts, which may suggest a direct link between pHe regulation and Pi transport activities during enamel
mineralization events. Data suggests that miRNAs, targeting the mRNAs of specific ion transport proteins,
also influence ion transport and pHe regulation. Our prior whole transcriptome analysis of maturation and
secretory enamel organ cells identify a potential role for miR-298 and miR-346 in the regulation of NHERF1,
Slc26a1, Slc26a7 and Cftr. In this application we hypothesize that a “SLC26A/CFTR/NHERF1/NaPi2b
network, directing ion movements directly related to HCO3- and Pi transport and pH regulation, while at the
same time dictating apical membrane architecture, is critical for enamel maturation, and disruptions to this
network result in enamel pathologies that will severely impact on enamel longevity.” We propose the following
specific aims: 1) immunolocalization of NHERF1, EZRIN, CFTR and NaPi2b in maturation ameloblasts; 2)
disrupt SLC26A/CFTR/NHERF1/NaPi2b network in enamel organ cells in vivo using miR-346 and miR-298
delivered directly at the site of mineralization; and; 3) investigate the nature of the NHERF1 and NaPi2b
interactions in enamel organ cells in vitro and in vivo. In this study we anticipate that disrupting the
SLC26A/CFTR network and NaPi2b activity, by directly targeting NHERF1 function, will result in a significant
enamel dysmorphology. Findings from this study will have a significant impact on our understanding of the
biomineralization process as it relates to enamel formation in all mammalian species. This study may also
lead to strategies for handling inherited enamel defects in the clinic; and, in the long run help to prevent and
alleviate the suffering of those afflicted with cystic fibrosis and other diseases.

## Key facts

- **NIH application ID:** 10193340
- **Project number:** 1R01DE029445-01A1
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Michael Lansdell Paine
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $352,688
- **Award type:** 1
- **Project period:** 2021-03-15 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10193340

## Citation

> US National Institutes of Health, RePORTER application 10193340, Amelogenesis and Ion Transport (1R01DE029445-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10193340. Licensed CC0.

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