Research Description
Highlights of Major Accomplishments
- Generation of corticotropin releasing hormone (CRH)-deficient (knockout) mice to demonstrate the role of CRH in circadian rhythmicity of the hypothalamic-pituitary-adrenal axis,
- Demonstration of CRH in placenta and likely role of CRH in the timing of fetal maturation and the onset of parturition,
-
Delineation of the role of vasopression in the mammalian stress response.
Major Results
1.
CRH
CRH-deficient (knockout) mice have been created by deletion of the CRH
gene. The perinatal death of these mice due to respiratory failure, and
its prevention by prenatal glucocorticoid treatment, provide the first
unambiguous proof of the requirement of glucocorticoid for normal lung
development. These studies define a major fetal role of this hormone to
be inhibition of alveolar epithelial cell proliferation rather than stimulation
of surfactant synthesis. With CRH knockout mice, we have defined the role
that CRH plays in the hormonal response to a variety of stressors. However,
we have found that stress-induced behaviors do not require CRH, but do
require a CRH receptor, suggesting that another CRH-related molecule mediates
behavioral stress responses. We have shown that urocortin, a CRH-like
molecule, is probably not involved in stress-induced behaviors, strongly
suggesting that a third, as yet undiscovered, CRH-like molecule has this
role in mammals. CRH deficiency leads to loss of circadian rhythmicity
of the hypothalamic-pituitary-adrenal axis, which is restored by replacement
with constant levels of CRH. This finding suggests that another factor,
possibly vasopressin, is responsible for the generation of circadian rhythmicity.
Using CRH knockout mice, we have also discovered a proinflammatory role
for epinephrine, to add to its other fight-or-flight functions. Further,
CRH-deficient mice have blunted secretion of adrenomedullary epinephrine,
likely due to their concomitant glucocorticoid deficiency. However, they
have normal reproductive responses to stress, indicating that CRH is not
required for this response. In addition, CRH has pro-angiogenic properties,
which may function to promote inflammation and wound healing in peripheral
sites.
CRH is also expressed at high levels in human placenta. We have found that CRH expression in cultured placental trophoblasts is stimulated by glucocorticoids and inhibited by progesterone, findings suggesting a mechanism whereby placental CRH may control both the timing of fetal maturation and the onset of parturition. These results provide a rationale for the different hormonal mechanisms of parturition which exist among different mammals, including a mechanism for progesterone withdrawal in humans.
The CRH gene is positively regulated by phosphorylated CREB. We have recently found that within cells, CREB binds only to the CRE of the CRH promoter following forskolin treatment, and that in the nonphosphorylated state, is not bound to DNA. This result suggests a general mechanism whereby phosphorylation affects the induction of gene expression.
We have extended our studies of the molecular endocrinology of the stress response by investigations of the regulation of the vasopressin gene, which, along with CRH, is a major hypothalamic regulator of the hypothalamic-pituitary-adrenal axis. In humans, we have studied the role of vasopressin in the response to a variety of stressors and the clinical impact of vasopressin gene mutations. Changes in both gene transcription and mRNA polyadenylate state were shown to interact to regulate vasopressin gene expression. In work not yet published, we have created vasopressin knockout mice. Mice with combined CRH and vasopressin deficiency are being constructed to delineate the respective roles of these two neuropeptides in the control of circadian and stress responses.
