Polysialic acid-directed migration and differentiation of neural precursors are essential for mouse brain development.
Polysialic acid, which is synthesized by two polysialyltransferases, ST8SiaII and ST8SiaIV, plays an essential role in brain development by modifying the neural cell adhesion molecule (NCAM). It is currently unclear how polysialic acid functions in different processes of neural development. Here we generated mice doubly mutant in both ST8SiaII and ST8SiaIV to determine the effects of loss of polysialic acid on brain development. In contrast to NCAM-deficient, ST8SiaII-deficient, or ST8SiaIV-deficient single mutant mice, ST8SiaII and ST8SiaIV double mutants displayed severe defects in anatomical organization of the forebrain associated with apoptotic cell death. Loss of polysialic acid affected both tangential and radial migration of neural precursors during cortical development, resulting in aberrant positioning of neuronal and glial cells. Glial cell differentiation was aberrantly increased in vivo and in vitro in the absence of polysialic acid. Consistent with these findings, polysialic acid-deficient mice exhibited increased expression of the glial cell marker glial fibrillary acidic protein and a decrease in expression of Pax6, a transcription factor regulating neural cell migration. These results indicate that polysialic acid regulates cell migration and differentiation of neural precursors crucial for brain development.
Angata
Kiyohiko
K
Glycobiology Program, Cancer Research Center, Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Huckaby
Valerie
V
Ranscht
Barbara
B
Terskikh
Alexey
A
Marth
Jamey D
JD
Fukuda
Minoru
M
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002454:Cell Differentiation; D002465:Cell Movement / Q000502:physiology*; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology* / Q000254:growth & development* / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000166:cytology / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012794:Sialic Acids / Q000378:metabolism*; D012799:Sialyltransferases / Q000235:genetics* / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*
D005136:Eye Proteins; D005904:Glial Fibrillary Acidic Protein; D018398:Homeodomain Proteins; D007527:Isoenzymes; D008164:Luminescent Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012097:Repressor Proteins; D012794:Sialic Acids; C021319:polysialic acid; C046778:CMP-N-acetylneuraminate-poly-alpha-2,8-sialosyl sialyltransferase; D012799:Sialyltransferases; C525848:ST8SiaIV protein, mouse