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Updated: Jun 25, 2026
Immunostaining to Visualize Murine Enteric Nervous System Development
Published on: April 29, 2015
Amphiregulin-deficient mice develop spasmolytic polypeptide expressing metaplasia and intestinal metaplasia
Ki Taek Nam1, Hyuk-Joon Lee, Hoyin Mok
1Nashville Department of Veterans Affairs Medical Center, Nashville, Tennessee 37232-0443, USA.
Background & Aims:
The loss of parietal cells from the fundic mucosa leads to the emergence of metaplastic lineages associated with an increased susceptibility to neoplastic transformation. Both intestinal metaplasia (IM) and spasmolytic polypeptide (TFF2/SP) expressing metaplasia (SPEM) have been identified in human stomach, but only SPEM is present in most mouse models of gastric metaplasia. We previously determined that loss of amphiregulin (AR) promotes SPEM induced by acute oxyntic atrophy. We have now examined whether SPEM in the AR-/- mouse predisposes the stomach to gastric neoplasia.
Methods:
Gross pathology of 18-month-old wild-type, AR-/-, and TGF-alpha-/- mice were examined. Ki-67, beta-catenin, Pdx-1, TFF3, and TFF2/SP expression was analyzed by immunohistochemistry. Metaplastic gastric mucosa was analyzed by dual immunostaining for TFF2/SP with MUC2 or TFF3.
Results:
By 18 months of age, more than 70% of AR-/- mice developed SPEM while 42% showed goblet cell IM labeled with MUC2, TFF3, and Pdx-1. A total of 28% had invasive gastric lesions in the fundus. No antral abnormalities were observed in AR-/- mice. Metaplastic cell lineages in AR-/- mice showed increases in cell proliferation and cytosolic beta-catenin expression. Dual staining for TFF2/SP with MUC2 or TFF3 showed glands containing both SPEM and IM with intervening cells expressing both TFF2/SP and MUC2 or TFF2/SP and TFF3.
Conclusions:
AR-/- mice develop SPEM, which gives rise to goblet cell IM and invasive fundic dysplastic lesions. The AR-/- mouse represents the first mouse model for spontaneous development of fundic SPEM with progression to IM.
Insights
Mice lacking amphiregulin (AR) spontaneously develop spasmolytic polypeptide-expressing metaplasia (SPEM), leading to intestinal metaplasia (IM) and invasive gastric lesions. This AR-/- mouse model shows progression from SPEM to IM, offering new insights into gastric cancer development.
Area of Science:
- Gastroenterology
- Oncology
- Molecular Biology
Background:
- Parietal cell loss in the fundic mucosa can lead to metaplasia and increased gastric cancer risk.
- Intestinal metaplasia (IM) and spasmolytic polypeptide (TFF2/SP) expressing metaplasia (SPEM) are known human gastric metaplasias.
- Loss of amphiregulin (AR) promotes SPEM after acute oxyntic atrophy.
Purpose of the Study:
- To investigate if SPEM in AR knockout (AR-/-) mice predisposes the stomach to gastric neoplasia.
- To establish a mouse model for spontaneous fundic SPEM with progression to IM.
Main Methods:
- Gross pathology examination of 18-month-old wild-type, AR-/-, and TGF-alpha-/- mice.
- Immunohistochemistry for Ki-67, beta-catenin, Pdx-1, TFF3, and TFF2/SP.
- Dual immunostaining for TFF2/SP with MUC2 or TFF3 to analyze metaplastic mucosa.
Main Results:
- AR-/- mice developed SPEM (in >70%) and goblet cell IM (in 42%) by 18 months.
- 28% of AR-/- mice exhibited invasive gastric lesions in the fundus; no antral abnormalities were noted.
- Metaplastic lineages in AR-/- mice showed increased proliferation and beta-catenin expression.
Conclusions:
- AR-/- mice spontaneously develop fundic SPEM, progressing to goblet cell IM and invasive dysplastic lesions.
- The AR-/- mouse is the first model to show spontaneous fundic SPEM with subsequent IM development.
- This model provides a valuable tool for studying the pathogenesis of gastric cancer initiated by SPEM.
