The notch target gene HES1 regulates cell cycle inhibitor expression in the developing pituitary.
The pituitary is an endocrine gland responsible for the release of hormones, which regulate growth, metabolism, and reproduction. Diseases such as hypopituitarism or pituitary adenomas are able to disrupt pituitary function leading to suboptimal function of the entire endocrine system. Growth of the pituitary during development and adulthood is a tightly regulated process. Hairy and enhancer of split (HES1), a transcription factor whose expression is initiated by the Notch signaling pathway, is a repressor of cell cycle inhibitors. We hypothesize that with the loss of Hes1, pituitary progenitors are no longer maintained in a proliferative state, choosing instead to exit the cell cycle. To test this hypothesis, we examined the expression of cell cycle regulators in wild-type and Hes1-deficient pituitaries. Our studies indicate that in early pituitary development [embryonic day (e) 10.5], cells contained in the Rathke's pouch of Hes1 mutants have decreased proliferation, indicated by changes in phosphohistone H3 expression. Furthermore, pituitaries lacking Hes1 have increased cell cycle exit, shown by significant increases in the cyclin-dependent kinase inhibitors, p27 and p57, from e10.5 to e14.5. Additionally, Hes1 mutant pituitaries have ectopic expression of p21 in Rathke's pouch progenitors, an area coincident with increased cell death. These observations taken together indicate a role for HES1 in the control of cell cycle exit and in mediating the balance between proliferation and differentiation, allowing for the properly timed emergence of hormone secreting cell types.
Monahan
Pamela
P
Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Rybak
Sabina
S
Raetzman
Lori T
LT
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology*; D002453:Cell Cycle / Q000235:genetics; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000096:biosynthesis*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D010902:Pituitary Gland / Q000196:embryology* / Q000378:metabolism; D000072056:Transcription Factor HES-1
D051792:Basic Helix-Loop-Helix Proteins; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D050761:Cyclin-Dependent Kinase Inhibitor p57; D018398:Homeodomain Proteins; D000072056:Transcription Factor HES-1; C493965:Cdkn1c protein, mouse; C489734:Hes1 protein, mouse