Notch signaling and cell cycle inhibitor regulation in pituitary organogenesis

Pituitary;Hes1;Cell Cycle;Development;Notch Signaling

Monahan, Pamela

关键词: Pituitary;    Hes1;    Cell Cycle;    Development;    Notch Signaling;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/24494/Monahan_Pamela.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

The pituitary is plastic organ whose hormone cell number can fluctuate depending on physiologic need. Alterations in pituitary cell expansion can lead to disorders such as pituitary hyperplasia or tumors, which have a high prevalence in the human population. Precise control of cell cycle progression is the molecular mechanism by which pituitary cell expansion is regulated. We have investigated signaling pathways active during development, a time of rapid organ growth, to understand the process of pituitary progenitor cell division. In development, progenitors choose between proliferation and cell cycle exit, followed by differentiation. Notch signaling has been shown to promote progenitor preservation, both through repression of differentiation as well as by directing proliferation. We show that the activated Notch pathway, through HES1, serves as a proliferative signal that promotes progenitor expansion, with its loss resulting in a severely hypomorphic pituitary.HES1 transcriptional repression of Cyclin Dependent Kinase Inhibitors (CDKI) is the mechanism by which HES1 promotes cell cycle progression. Loss of Hes1 in the developing pituitary, results in increased expression of the CDKIs p21, p27 and p57. We hypothesize that this aberrant increase in expression may be a molecular mechanism contributing to progenitor pool depletion. Increased expression of CDKIs has been shown to be a hallmark of differentiating cells and loss of CDKIs has been shown to potentiate tumorigenesis of the pituitary in adult life in humans and rodent models. Studies by other groups have shown that p57 and p27 are CDKIs that modulate proliferation in the growing embryonic pituitary. With our studies now show that these molecules are not the sole contributors and that p21 may also be responsible for controlling pituitary proliferation. To uncover the individual and overlapping roles of CDKIs in regulating pituitary cell number, we examined the pituitaries of mice lacking p21 and p27 alone, as well as double mutants.Loss of both p21 and p27 drastically increases proliferation throughout the developing pituitary, indicating that expression of these molecules is crucial to controlling pituitary progenitor cell expansion. Taken together, these studies suggest that Notch regulatory pathway activation is necessary for fine-tuning a balance between proliferation and differentiation by modulating CDKI expression during embryonic pituitary and that CDKI action is needed to restrain proliferative signaling preventing excess proliferation or even tumor formation.