Tsiarli, Maria
(2014)
DISSECTING THE ROLE OF THE GLUCOCORTICOID RECEPTOR IN EMBRYONIC CORTICAL DEVELOPMENT: INSIGHTS FROM IN UTERO GLUCOCORTICOID EXPOSURE.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Synthetic glucocorticoids (GCs) such as dexamethasone (DEX), are given to pregnant women to reduce the incidence of respiratory distress syndrome and intraventricular hemorrhage in premature infants. However, animal and human studies reveal adverse effects of DEX on cerebral cortical development. Understanding the basis for these negative neurological consequences of prenatal GCs would be aided by a detailed description of the developmental and spatial expression profile of the glucocorticoid receptor (GR) in neural stem/progenitor cells. This could provide mechanistic understanding of the impact of premature activation of GR signaling in the developing brain, particularly since endogenous GC levels are low during the period of fetal development at which DEX is administered. In this study we show that GR protein is expressed in cortical radial glia cells (RGCs) and intermediate progenitor cells (IPCs) from embryonic day 11.5 in the mouse. Furthermore, in many areas of the fetal brain, GR was primarily nuclear at times when endogenous GCs are expected to be low. We also examined the consequences of prenatal DEX exposure and found that a single, clinically relevant DEX dose at midgestation (E14.5) reduced cortical thickness and surface on E17.5, but increased the number of neurons throughout the cortex, including in deep layer VI. BrdU birthdating revealed that the BrdU+ progeny of the E14.5 progenitors was increased by DEX. Furthermore, while a higher proportion migrated in the cortical plate, a smaller proportion remained in the progenitor zone, suggesting that DEX promoted precocious neurogenesis. Accordingly, after a single, 24 hour exposure on E14.5, DEX induced a neurogenic fate shift in progenitors in an S-phase-specific manner. Specifically in non-S-RGCs DEX promoted the IPC fate, while it induced re-entry of S-phase RGCs and expansion primarily of the neurogenic RGC pool (BrdU+). DEX induced neurogenic divisions of S-phase RGCs and S-phase IPCs causing increase of the BrdU+ cells. FACs analysis verified the neurogenic shift in S-phase BrdU+ progenitors, which accumulated in G0G1 phase. Collectively, these results suggest that premature, DEX-induced activation of GR induces cell cycle phase-dependent precocious neurogenesis and highlights a role for GR in regulating neurogenesis in the developing brain.
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| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
25 September 2014 |
| Date Type: |
Publication |
| Defense Date: |
2 June 2014 |
| Approval Date: |
25 September 2014 |
| Submission Date: |
16 July 2014 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
181 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Dietrich School of Arts and Sciences > Neuroscience |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
embryo, neurogenesis, cerebral cortex, glucocorticoids, dexamethasone, neural progenitors |
| Date Deposited: |
25 Sep 2014 16:38 |
| Last Modified: |
23 Mar 2018 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/22343 |
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