Abstract
Proximal renal tubular acidosis (pRTA) is a syndrome caused by abnormal proximal tubule reabsorption of bicarbonate resulting in metabolic acidosis. Patients with mutations to the SLC4A4 gene (coding for the sodium bicarbonate cotransporter NBCe1), have pRTA, growth delay, ocular defects, and enamel abnormalities. In an earlier report, we provided the first evidence that enamel cells, the ameloblasts, express NBCe1 in a polarized fashion, thereby contributing to trans-cellular bicarbonate transport. To determine whether NBCe1 plays a critical role in enamel development, we studied the expression of NBCe1 at various stages of enamel formation in wild-type mice and characterized the biophysical properties of enamel in NBCe1(-/-) animals. The enamel of NBCe1(-/-) animals was extremely hypomineralized and weak with an abnormal prismatic architecture. The expression profile of amelogenin, a known enamel-specific gene, was not altered in NBCe1(-/-) animals. Our results show for the first time that NBCe1 expression is required for the development of normal enamel. This study provides a mechanistic model to account for enamel abnormalities in certain patients with pRTA.
Highlights
Enamel development can be subdivided into three major functional stages: presecretion, secretion, and maturation [1]
We provided the first evidence that enamel cells, the ameloblasts, express NBCe1 in a polarized fashion, thereby contributing to trans-cellular bicarbonate transport
Winsnes and collaborators reported the cases of two brothers with severe hyperchloremic acidosis, a maximum tubular capacity for bicarbonate reabsorption about half normal, growth and mental retardation, nystagmus, cataract, corneal opacities, 24436 JOURNAL OF BIOLOGICAL CHEMISTRY
Summary
Animals and Animal Husbandry—All vertebrate animal manipulation complied with institutional and federal guidelines. Role of NBCe1 in Amelogenesis for study were sacrificed at between 12–14 days post-natal This is the time at which the life expectancy of NBCe1Ϫ/Ϫ animals declines drastically [6]. Tissue Dissection and RT-PCR—Ameloblasts from the late secretory stage of 7-day-old mice were dissected from mandibular incisors following protocols described previously [10, 11]. Scanning Electron Microscopy (SEM)—For SEM analyses, the heads of mice from the various experimental group ages (12– 14-day-old) were fixed by immersion in 4% paraformaldehyde overnight and placed in phosphate-buffered saline. Some polished samples were coated with carbon in a Baltec MED 020 coating system (Balzers AG) and examined using the backscattered electron detector in a JEOL 7400F field emission scanning electron microscope operated at 20 kV. Descriptive statistics, one-way analysis of variance (p Ͻ 0.05), and Tukey multiple comparisons testing (p Ͻ 0.05) were used to analyze the data
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