Darryl Hadsell, Ph.D.
Departments of Pediatrics and Molecular and Cellular Biology
Ph.D.: The Pennsylvania State University, State College
Postdoctoral training: Baylor College of Medicine, Houston
Molecular Pathways in the Regulation of Lactation
The regulation of mammary cell turnover function during lactation involves interactions between signaling pathways that regulate cell cycle progression, cell differentiation, cell metabolic rate, and cell death. These interactions are not simply events which occur within the secretory epithelial cell, but involve other cell types within the mammary gland as well. In addition, the process is regulated not only by the genetic background of the lactating female but also by environmental factors such as age, diet, and body composition My laboratory uses state-of-the-art immunohistochemical and imaging techniques along with genomic and proteomic strategies to determine the relationships between in-vivo developmental processes that occur in the lactating mammary gland and the gene expression and metabolic events that regulate them. Dietary strategies along with transgenic and knockout mouse models are used to determine the impact of perturbing specific signaling or metabolic pathways on the regulation of postpartum mammary cell turnover.
Our work on IGF-I action suggests that variation signaling pathway use by the IGF-I receptor (Igf1r) occurs at different developmental stages. During lactation IGF-I relies on cell survival pathways to inhibit mammary cell apoptosis while during earlier stages of development IGF-I action occurs through proliferative pathways. The regulation of apoptosis in the lactating secretory cell is known to involve intrinsic regulation through the mitochondria. Our recent studies on mitochondrial biogenesis and function in the mammary gland suggest that oxidative damage to secretory cell mitochondria may play a significant role in causing the decline in milk synthesis capacity that occurs with progression through lactation. Along with these observations, microarray analysis is being used to identify gene pathways within the mammary gland that regulate the loss of milk synthesis capacity that is known to occur during prolonged lactation and maternal obesity. These studies have identified potential roles not only for metabolic signaling within the secretory cell but also for actions of other cells types such as macrophages.
Baylor College of Medicine
One Baylor Plaza
Houston, TX 77030
- Hadsell DL, Olea W, Lawrence N, George J, Torres D, Kadowaki T and Lee AV. (2007). Decreased lactation capacity and altered milk composition in insulin receptor substrate null mice is associated with decreased insulin-dependent phosphorylation of Akt. J. Endocrinol. 194(2):327-336.
- Hadsell DL, George J and Torres D. (2007). The declining phase of lactation; peripheral of central, programmed or pathological. J. Mammary Gland Biol. Neoplasia. 12:59-70.
- Hadsell DL, Torres D, George J, Capuco AV and Fiorotto ML. (2006). Changes in secretory cell turnover, and mitochondrial oxidative damage in the mouse mammary gland during a single prolonged lactation cycle suggest the possibility of accelerated cellular aging. Exp. Gerontology 41(3):271-81.
- Hadsell DL, Torres D, Lawrence NA, George J, Shelton GS, Parlow AF, Fiorotto ML and Lee AV. (2005). Overexpression des(1-3)hIGF-I in the Mammary Gland during prolonged lactation enhances milk yield and elevates blood prolactin. Biol. Reprod. 73(6):1116-25.
- Hadsell DL. (2004). Genetic manipulation of mammary gland development and lactation. Advances Exp Med Biol 554:229-251.
- Hadsell DL, Bonnette SG, George J, Torres D, Klementidis Y, Gao S, Haney PM, Sumy-Long J, Soloff M, Parlow AF, Sirito M and Sawadogo M. (2003). Diminished milk synthesis in upstream stimulatory factor 2 (usf2) null mice is associated with decreased circulating oxytocin and decreased mammary gland expression of eukaryotic initiation factors (eIF) 4E and 4G. Mol Endocrinol 17(11):2251-2267.
- Lee AV, Taylor S, Greenall J, Mills J, Tonge D, Fiorotto M and Hadsell DL. (2004). Rapid induction of IGF-IR signalling in normal and tumor tissue following intravenous injection of IGF-I. Hormone Metab Res 35:651-655.
- Lee AV, Zhang P, Ivanova M, Bonnette S, Oesterreich S, Rosen JM, Grimm S, Hovey RC, Vonderhaar BK, Kahn CR ,Torres D, George J, Mohsin S, Allred DC and Hadsell DL. (2003). Developmental and hormonal signals dramatically alter the localization and abundance of insulin receptor substrate proteins in the mammary gland. Endocrinology 144(6):2683-2694.
- Hadsell DL, Bonnette SG and Lee AV. (2002). Genetic manipulation of the IGF-I axis to regulate mammary gland development and function. J. Dairy Sci. 85:365-377.
- Hadsell DL, Alexeenko T, Klemintidis YK, Torres D and Lee AV. (2001). Inability of overexpressed des(1-3)hIGF-I to inhibit forced mammary gland involution is associated with decreased abundance of IGF signaling molecules. Endocrinology 142(4):1479-1488.