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Temporospatial aberrations of apoptosis in the rat embryo developing esophageal atresia
A K Williams1, B Q Qi, S W Beasley
1Department of Paediatric Surgery, Christchurch Hospital, Christchurch School of Medicine, New Zealand.
Insights
A lack of apoptosis during critical foregut development, not altered patterns, causes esophageal atresia and tracheoesophageal fistula (EA-TEF) in rats. This suggests apoptosis may be a response to abnormal development, not the cause.
Area of Science:
- Developmental Biology
- Cell Biology
- Teratology
Background:
- Apoptosis is crucial for normal foregut development.
- Esophageal atresia and tracheoesophageal fistula (EA-TEF) are congenital abnormalities of the foregut.
Purpose of the Study:
- To compare apoptosis patterns in normal developing rat foregut versus fetuses with EA-TEF.
- To investigate the role of apoptosis in the etiology of EA-TEF using 3D reconstruction.
Main Methods:
- Timed pregnant rats were administered Adriamycin to induce EA-TEF or left untreated (controls).
- Embryos (days 11-14 gestation) underwent serial sectioning and H&E staining.
- 3D reconstructions of the foregut were created to map apoptotic patterns.
Main Results:
- Normal apoptosis occurred during tracheoesophageal separation (days 12-12.5) in controls.
- Adriamycin-exposed embryos showed delayed apoptosis (day 13) in the esophageal and laryngeal mesenchyme.
- No apoptosis was observed in the developing foregut epithelium of experimental embryos.
Conclusions:
- The timing and location of apoptosis are abnormal in rat fetuses developing EA-TEF.
- A complete absence of apoptosis at a critical developmental stage appears to cause EA-TEF.
- Apoptosis observed in the mesenchyme might be a secondary reaction to abnormal development rather than the primary cause.
Background/Purpose:
Recent work has shown that apoptosis is a key component of the normal development of the foregut. This study was designed to compare the patterns of apoptosis in the normal foregut with those in the fetus developing esophageal atresia and tracheoesophageal fistula (EA-TEF) using 3-dimensional reconstructive techniques.
Methods:
Timed pregnant rats that received no treatment (control group) or received Adriamycin intraperitoneally (experimental group) had their embryos removed between days 11 and 14 of gestation. The embryos were sectioned serially and stained with H&E. Three-dimensional reconstructions were made of the foregut and areas of apoptosis were marked on them to facilitate analysis of apoptotic patterns.
Results:
Apoptosis was evident in control embryos in the region in which tracheoesophageal separation occurs from days 12 and 12.5. Experimental embryos showed no apoptosis until day 13 when apoptosis was observed immediately posterior to the foregut within the esophageal mesenchyme and in the laryngeal mesenchyme ventral to the foregut.
Conclusions:
The pattern, timing and location of apoptosis in rats developing EA-TEF is abnormal. Our work indicates that it is actually a complete lack of apoptosis at the crucial stage of development that leads to this abnormality rather than an alteration in the patterning of apoptosis at this crucial time. The observation of apoptosis only within the mesenchyme raises the possibility that apoptosis in the foregut developing EA-TEF may be a reaction to that abnormal development rather than its cause.