Loss of the heparan sulfate sulfotransferase, Ndst1, in mammary epithelial cells selectively blocks lobuloalveolar development in mice.
BACKGROUND
Considerable evidence indicates that heparan sulfate is essential for the development of tissues consisting of branching ducts and tubules. However, there are few examples where specific sulfate residues regulate a specific stage in the formation of such tissues.


RESULTS
We examined the role of heparan sulfation in mammary gland branching morphogenesis, lactation and lobuloalveolar development by inactivation of heparan sulfate GlcNAc N-deacetylase/N-sulfotransferase genes (Ndst) in mammary epithelial cells using the Cre-loxP system. Ndst1 deficiency resulted in an overall reduction in glucosamine N-sulfation and decreased binding of FGF to mammary epithelial cells in vitro and in vivo. Mammary epithelia lacking Ndst1 underwent branching morphogenesis, filling the gland with ductal tissue by sexual maturity to the same extent as wildtype epithelia. However, lobuloalveolar expansion did not occur in Ndst1-deficient animals, resulting in insufficient milk production to nurture newly born pups. Lactational differentiation of isolated mammary epithelial cells occurred appropriately via stat5 activation, further supporting the notion that the lack of milk production was due to lack of expansion of the lobuloalveoli.


CONCLUSIONS
These findings demonstrate a selective, highly penetrant, cell autonomous effect of Ndst1-mediated sulfation on lobuloalveolar development.
Crawford
Brett E
BE
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California, United States of America.
Garner
Omai B
OB
Bishop
Joseph R
JR
Zhang
David Y
DY
Bush
Kevin T
KT
Nigam
Sanjay K
SK
Esko
Jeffrey D
JD
D000818:Animals; D004847:Epithelial Cells / Q000201:enzymology* / Q000473:pathology*; D005260:Female; D020868:Gene Silencing; D018390:Gene Targeting; D019426:Integrases / Q000378:metabolism; D007774:Lactation; D008321:Mammary Glands, Animal / Q000254:growth & development* / Q000473:pathology* / Q000637:transplantation; D008324:Mammary Tumor Virus, Mouse / Q000378:metabolism; D051379:Mice; D009024:Morphogenesis; D013194:Staining and Labeling; D015238:Sulfotransferases / Q000172:deficiency* / Q000378:metabolism; D013455:Sulfur / Q000378:metabolism
D013455:Sulfur; C045073:Cre recombinase; D019426:Integrases; D015238:Sulfotransferases; C021350:heparitin sulfotransferase