We have examined the role of heparan sulfate in mammary gland branching morphogenesis and lactation by tissue-specific deletion of heparan sulfate GlcNAc N-deacetylase/N-sulfotransferase-1 (NDST1) in wildtype and NDST2 null mice. Mammary epithelia lacking both isozymes failed to undergo branching morphogenesis, whereas epithelia lacking only NDST1 developed normally to sexual maturity but did not undergo lobuloalveolar expansion during pregnancy. The epithelia of NDST1 deficient glands were highly apoptotic at day 1 of lactation, exhibiting reduced phosphorylation of AKT/PKB, decreased cyclin D1 expression, and hyperphosphorylation of Erk1/2. In vitro experiments suggested that undersulfation of heparan sulfate disrupted heregulin signaling through ErbB receptors. These findings show that NDST1 or NDST2 are sufficient for branching morphogenesis in the mammary gland, but NDST1 is required for lobuloalveolar development. We attribute these differences to unique patterns of sulfation of the chains affected by these two enzymes.
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