NDLI: Tumorigenic fragments of APC cause dominant defects in directional cell migration in multiple model systems

Content Provider	PubMed Central
Author	Nelson, Scott A. Li, Zhouyu Newton, Ian P. Fraser, David Milne, Rachel E. Martin, David M. A. Schiffmann, David Yang, Xuesong Dormann, Dirk Weijer, Cornelis J. Appleton, Paul L. Näthke, Inke S.
Copyright Year	2012
Abstract	Nonsense mutations that result in the expression of truncated, N-terminal, fragments of the adenomatous polyposis coli (APC) tumour suppressor protein are found in most sporadic and some hereditary colorectal cancers. These mutations can cause tumorigenesis by eliminating β-catenin-binding sites from APC, which leads to upregulation of β-catenin and thereby results in the induction of oncogenes such as MYC. Here we show that, in three distinct experimental model systems, expression of an N-terminal fragment of APC (N-APC) results in loss of directionality, but not speed, of cell motility independently of changes in β-catenin regulation. We developed a system to culture and fluorescently label live pieces of gut tissue to record high-resolution three-dimensional time-lapse movies of cells in situ. This revealed an unexpected complexity of normal gut cell migration, a key process in gut epithelial maintenance, with cells moving with spatial and temporal discontinuity. Quantitative comparison of gut tissue from wild-type mice and APC heterozygotes (APCMin/+ ; multiple intestinal neoplasia model) demonstrated that cells in precancerous epithelia lack directional preference when moving along the crypt-villus axis. This effect was reproduced in diverse experimental systems: in developing chicken embryos, mesoderm cells expressing N-APC failed to migrate normally; in amoeboid Dictyostelium, which lack endogenous APC, expressing an N-APC fragment maintained cell motility, but the cells failed to perform directional chemotaxis; and multicellular Dictyostelium slug aggregates similarly failed to perform phototaxis. We propose that N-terminal fragments of APC represent a gain-of-function mutation that causes cells within tissue to fail to migrate directionally in response to relevant guidance cues. Consistent with this idea, crypts in histologically normal tissues of APCMin/+ intestines are overpopulated with cells, suggesting that a lack of migration might cause cell accumulation in a precancerous state.
Related Links	http://dx.doi.org/10.1242/dmm.008607
Ending Page	947
Page Count	8
Starting Page	940
File Format	PDF
ISSN	17548403
e-ISSN	17548411
Journal	Disease Models & Mechanisms
Issue Number	6
Volume Number	5
Language	English
Publisher	The Company of Biologists Limited
Publisher Date	2012-11-01
Access Restriction	Open
Rights Holder	The Company of Biologists Limited
Subject Keyword	Immunology and Microbiology (miscellaneous) Biochemistry, Genetics and Molecular Biology(all) Medicine (miscellaneous) Neuroscience (miscellaneous) Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Neuroscience Immunology and Microbiology Medicine Biochemistry, Genetics and Molecular Biology

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

Auditory hair cell defects as potential cause for sensorineural deafness in Wolf-Hirschhorn syndrome

Genetic interactions between planar cell polarity genes cause diverse neural tube defects in mice

Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects

Oogenesis defects in a mutant mouse model of oculodentodigital dysplasia

Phenotype-driven chemical screening in zebrafish for compounds that inhibit collective cell migration identifies multiple pathways potentially involved in metastatic invasion

Reduction of pro-tumorigenic activity of human prostate cancer-associated fibroblasts using Dlk1 or SCUBE1

From bench to patient: model systems in drug discovery

Excessive activity of cathepsin K is associated with cartilage defects in a zebrafish model of mucolipidosis II

Cell culture and Drosophila model systems define three classes of anaplastic lymphoma kinase mutations in neuroblastoma

Tumorigenic fragments of APC cause dominant defects in directional cell migration in multiple model systems

Similar Documents

Auditory hair cell defects as potential cause for sensorineural deafness in Wolf-Hirschhorn syndrome

Genetic interactions between planar cell polarity genes cause diverse neural tube defects in mice

Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects

Oogenesis defects in a mutant mouse model of oculodentodigital dysplasia

Phenotype-driven chemical screening in zebrafish for compounds that inhibit collective cell migration identifies multiple pathways potentially involved in metastatic invasion

Reduction of pro-tumorigenic activity of human prostate cancer-associated fibroblasts using Dlk1 or SCUBE1

From bench to patient: model systems in drug discovery

Excessive activity of cathepsin K is associated with cartilage defects in a zebrafish model of mucolipidosis II

Cell culture and Drosophila model systems define three classes of anaplastic lymphoma kinase mutations in neuroblastoma

Tumorigenic fragments of APC cause dominant defects in directional cell migration in multiple model systems