Adenomatous polyposis coli is required for early events in the normal growth and differentiation of the developing cerebral cortex.
BACKGROUND
Adenomatous polyposis coli (Apc) is a large multifunctional protein known to be important for Wnt/beta-catenin signalling, cytoskeletal dynamics, and cell polarity. In the developing cerebral cortex, Apc is expressed in proliferating cells and its expression increases as cells migrate to the cortical plate. We examined the consequences of loss of Apc function for the early development of the cerebral cortex.


RESULTS
We used Emx1(Cre) to inactivate Apc specifically in proliferating cerebral cortical cells and their descendents starting from embryonic day 9.5. We observed reduction in the size of the mutant cerebral cortex, disruption to its organisation, and changes in the molecular identity of its cells. Loss of Apc leads to a decrease in the size of the proliferative pool, disrupted interkinetic nuclear migration, and increased apoptosis. beta-Catenin, pericentrin, and N-cadherin proteins no longer adopt their normal high concentration at the apical surface of the cerebral cortical ventricular zone, indicating that cell polarity is disrupted. Consistent with enhanced Wnt/beta-catenin signalling resulting from loss of Apc we found increased levels of TCF/LEF-dependent transcription and expression of endogenous Wnt/beta-catenin target genes (Axin2 (conductin), Lef1, and c-myc) in the mutant cerebral cortex. In the Apc mutant cerebral cortex the expression of transcription factors Foxg1, Pax6, Tbr1, and Tbr2 is drastically reduced compared to normal and many cells ectopically express Pax3, Wnt1, and Wt1 (but not Wnt2b, Wnt8b, Ptc, Gli1, Mash1, Olig2, or Islet1). This indicates that loss of Apc function causes cerebral cortical cells to lose their normal identity and redirect to fates normally found in more posterior-dorsal regions of the central nervous system.


CONCLUSIONS
Apc is required for multiple aspects of early cerebral cortical development, including the regulation of cell number, interkinetic nuclear migration, cell polarity, and cell type specification.
Ivaniutsin
Uladzislau
U
Genes and Development Group, Centre for Integrative Physiology, School of Biomedical Sciences, The University of Edinburgh, Edinburgh, UK. u.ivaniutsin@gmail.com
Chen
Yijing
Y
Mason
John O
JO
Price
David J
DJ
Pratt
Thomas
T
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000941:Antigens / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D015820:Cadherins / Q000378:metabolism; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000502:physiology*; D002540:Cerebral Cortex / Q000254:growth & development* / Q000378:metabolism; D004622:Embryo, Mammalian; D005453:Fluorescence; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism; D000099260:Empty Spiracles Homeobox Proteins
D025601:Adenomatous Polyposis Coli Protein; D000941:Antigens; D015820:Cadherins; D018398:Homeodomain Proteins; D014157:Transcription Factors; D051176:beta Catenin; D001616:beta-Galactosidase; D000099260:Empty Spiracles Homeobox Proteins; C086178:pericentrin