Morphogenesis and Regeneration
The mammary gland develops postnatally and undergoes regression and amplification under the control of endocrine hormones, estrogen, progesterone, growth hormone, and prolactin. Like most other endocrine factors, these hormones do not bind to heparan sulfate but rather act on the mammary stroma to induce the local expression of soluble growth factors, many of which bind to heparan sulfate. Reducing the extent of sulfation specifically in the mammary epithelia using the Cre-loxP system had no effect on the viability or expected Mendelian ratio of offspring, but the pups failed to survive due to insufficient lactation by the mothers. Normal primary ductal proliferation and branching occurred, but a striking deficiency in lobuloalveolar development was manifest. In other studies we found that deletion of all sulfation or the inhibition of heparan sulfate polymerization prevented earlier stages in branching morphogenesis. Studies are underway to determine the primary growth factor signaling deficiencies responsible for these defects. The studies complement the branching system in the kidney under study in Sanjay Nigam’s laboratory.
The liver has amazing capacity to regenerate after physical or chemical damage. After surgical ablation of two-thirds of the liver, it will regenerate within 7-10 days, reestablishing the appropriate architecture and liver mass/body ratio. This process appears to involve minimal cell division and extensive hypertrophy of existing hepatocytes. In contrast, chemical damage induces stem cell division and regeneration of all cell lineages (endothelial cells, hepatocytes, etc.). The role of proteoglycans in hypertrophy and hyperproliferation are unknown, but we suspect an important role based on the nature of the growth factors thought to participate in regeneration. Current studies focus on the behavior of various proteoglycan deficient mutants in these models of liver injury. Analysis of the system is an ongoing collaboration with Lola Reid at the University of North Carolina.
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