Michelsohn, Arie M. (1992) Sequential steps in the determination of chromaffin cell fate by glucocorticoids. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechTHESIS:08242011-162533018
The development of the sympathoadrenal (SA) lineage has been studied as a model system in which to investigate the mechanisms that control the timing of environmental influences on cell fate. Glucocorticoids (GC) play a key role in the fate of the SA progenitor, causing it to differentiate to an adrenal chromaffin cell, rather than to a sympathetic neuron. Previously, it has been shown that GC exert both positive and negative effects on developing chromaffin cells: they promote cell survival and the expression of an adrenergic phenotype, and inhibit the expression of neuronal properties. However, the time at which GC first influence cell fate, and the mechanism(s) which underlie its effect(s), have remained matters of controversy. In this thesis, it is shown that the positive and negative effects of GC on SA progenitors during development are temporally separated and pharmacologically distinct. Most SA progenitors are competent to respond to GC by inhibition of process outgrowth two days before they are competent to respond by induction of PNMT, a chromaffm-specific marker. Competence to express PNMT appears to be acquired according to a cell-autonomous "clock". The early inhibition of neuronal differentiation may be a prerequisite to subsequent PNMT expression, since sympathetic neuroblasts rapidly lose the capacity to express PNMT. The two effects of GC are both mediated via the type-II glucocorticoid receptor (GCR). However, lower concentrations of GC are required to inhibit neuronal differentiation than to promote the expression of PNMT, and the two effects show differential responsiveness towards the receptor-specific antagonist RU38486. That the two effects of GC in this system are pharmacologically separable suggests that they may be mediated via different interactions of the GCR with endogenous cellular transcription machinery. Such differential interactions may explain how the two effects of GC in this system are temporally separated. Taken together, the results presented here provide precedent for an inductive developmental event in which the timing of the effects of an instructive signal on a bipotential progenitor are controlled neither by the schedule of appearance of the signal, nor of its receptor, but rather by cell-intrinsic, developmental changes in the response properties of the cell.
|Item Type:||Thesis (Dissertation (Ph.D.))|
|Degree Grantor:||California Institute of Technology|
|Thesis Availability:||Restricted to Caltech community only|
|Defense Date:||7 October 1991|
|Default Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||Benjamin Perez|
|Deposited On:||25 Aug 2011 16:57|
|Last Modified:||26 Dec 2012 04:38|
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