The pituitary gland coordinates growth, fertility, metabolism and the stress response through release of hormones from small numbers of highly specialized cells. A delicate balance between cell division and differentiation, in part regulated by hormonal milieu, dictates pituitary gland size. There is a lack of understanding of the molecular pathways controlling progenitor cell behavior, and thus pituitary cell number, beyond embryogenesis. This gap in knowledge must be filled because pituitary diseases presenting with too few hormone producing cells (hypopituitarism) and too many cells (adenomas) represent a substantial health burden, with the prevalence of adenomas alone being 1 in 1,100. The long-term goal is to define the signaling pathways controlling proliferation of pituitary progenitor cels to understand the pathology behind hypopituitarism and pituitary tumors. The objective of this application is to determine the mechanism by which pituitary progenitor/stem cells are maintained in the postnatal and adult gland and the signals that control their expansion and differentiation. The central hypothesis is that Notch signaling in pituitary progenitors is necessary to maintain them in an undifferentiated state and to promote their proliferation in a context specific manner. Preliminary and published data from the applicant's lab support the proposed role of Notch signaling. The hypothesis that Notch is an integral component of pituitary progenitor cell behavior will be tested by pursuing three specific aims: 1) Determine the mechanism by which the balance between progenitor maintenance and differentiation is controlled during pituitary gland expansion after birth. 2) Determine the mechanism by which progenitor cells are maintained and mobilized in the adult pituitary gland. 3) Elucidate how endogenous hormone feedback loops can alter proliferation of pituitary cells. In each of these aims, proliferation and differentiation of pituitary progenitor cells will be assessed in vivo in te context of temporally controlled gain and loss of function of Notch signaling. Stem/progenitor cells in the postnatal and adult pituitary have only recently been described. This proposed research would advance the understanding of signaling pathways that integrate to control the activity of these progenitor cells. Based on the fact that therapies targeting Notch signaling are in early stage clinical trials for leukemia and breast cancer, there is the potential for the basic understanding of Notch action in pituitary progenitors to lead to treatment of pituitary tumors.
Pituitary size anomalies, either hypoplasia or tumor growth, result in infertility, impaired stress response due to dysregulated cortisol secretion, and alterations in growth and metabolism. The proposed research will uncover the fundamental mechanism by which Notch signaling activity influences pituitary cell number, thus possibly identifying a point to intervene to increase or decrease cell number in the gland to reduce the associated morbidity and mortality with these common endocrine diseases.
|Nantie, Leah B; Himes, Ashley D; Getz, Dan R et al. (2014) Notch signaling in postnatal pituitary expansion: proliferation, progenitors, and cell specification. Mol Endocrinol 28:731-44|
|Aujla, Paven K; Naratadam, George T; Xu, Liwen et al. (2013) Notch/Rbpj* signaling regulates progenitor maintenance and differentiation of hypothalamic arcuate neurons. Development 140:3511-21|
|Monahan, Pamela; Himes, Ashley D; Parfieniuk, Agata et al. (2012) p21, an important mediator of quiescence during pituitary tumor formation, is dispensable for normal pituitary development during embryogenesis. Mech Dev 128:640-52|
|Goldberg, Leah B; Aujla, Paven K; Raetzman, Lori T (2011) Persistent expression of activated Notch inhibits corticotrope and melanotrope differentiation and results in dysfunction of the HPA axis. Dev Biol 358:23-32|
|Aujla, Paven K; Bora, Adriana; Monahan, Pamela et al. (2011) The Notch effector gene Hes1 regulates migration of hypothalamic neurons, neuropeptide content and axon targeting to the pituitary. Dev Biol 353:61-71|
|Himes, Ashley D; Fiddler, Rachel M; Raetzman, Lori T (2011) N-cadherin loss in POMC-expressing cells leads to pituitary disorganization. Mol Endocrinol 25:482-91|
|Moran, Tyler B; Goldberg, Leah B; Serviss, Sarah L et al. (2011) Numb deletion in POMC-expressing cells impairs pituitary intermediate lobe cell adhesion, progenitor cell localization, and neuro-intermediate lobe boundary formation. Mol Endocrinol 25:117-27|
|Monahan, Pamela; Rybak, Sabina; Raetzman, Lori T (2009) The notch target gene HES1 regulates cell cycle inhibitor expression in the developing pituitary. Endocrinology 150:4386-94|
|Himes, Ashley D; Raetzman, Lori T (2009) Premature differentiation and aberrant movement of pituitary cells lacking both Hes1 and Prop1. Dev Biol 325:151-61|