Altered regulation of CRF pathways CRFBP transgenic mice

As discussed above, CRF-BP binds CRF and urocortin 1 with an affinity equal to or greater than the CRF, receptor (Behan et al., 1989; Potter et al., 1991; Cortright et al., 1995), leading to the postulate that this molecule may regulate CRF actions in vivo by clearance of CRF and reduced availability for binding to CRF receptors. However, while the affinity of CRF for CRF, receptors and CRF-BP is similar, CRF interacts with CRF-BP with slower kinetics. Thus, an interaction between CRF and pituitary CRF-BP may not occur rapidly enough to affect CRFi receptor signaling (Linton et al., 1990). Two CRF-BP transgenic models have been created to address the physiologic role of CRF-BP. One transgenic model (a-GSU-CRF-BP) was created using CRF-BP cDNA linked to the pituitary glycoprotein hormone a-subunit (a-GSU) promoter to specifically enhance anterior pituitary expression (Burrows et al, 1998). Accordingly, the CRF-BP trangene is highly expressed in gonadotropes and thyrotropes. In this model, CRF-BP secretion from these cells was postulated to bind CRF in extracellular regions surrounding corticotropes (Potter et al., 1992). The second transgenic model, mMT-CRF-BP, was created using rat CRF-BP cDNA under the control of the mouse metallothionein promoter (mMT-1) (Lovejoy et al., 1998). These mice express the transgene in several brain regions including olfactory lobes, forebrain, brain stem, and pituitary as well as ectopically in the liver, heart, lung, kidney, spleen, adrenals, and testes. In addition, CRF-BP is detectable in the blood.

HPA axis activity appears relatively normal in these transgenic models as basal levels of circulating ACTH and corticosterone are similar to WT mice (Burrows et al., 1998; Lovejoy et al., 1998). However, a-GSU CRF-BP Tg mice exhibit significantly higher CRF and AVP mRNA in the PVN, suggesting that the CRF-BP transgene is able to reduce available CRF but compensatory mechanisms are initiated rapidly to increase CRF synthesis (Burrows et al., 1998). This conclusion is somewhat speculative as free CRF was not measured in the pituitary. Nonetheless, these findings suggest that endogenous CRF-BP may play a role in regulating basal HPA axis tone, which may be masked by tight feedback control. Neuroendocrine responses to stress do not appear to be modified by pituitary CRF-BP because a-GSU CRF-BP mice show normal stress-induced increases in ACTH and corticosterone. However, in mMT-CRF-BP mice, the ACTH response to LPS injection is diminished compared to WT mice (Lovejoy et al., 1998). In this situation, LPS further increases CRF-BP transgene expression, likely due to the mMT-1 promoter, which is responsive to immune activation. Thus, supra-physiologic levels of circulating CRF-BP were able to suppress HPA activation.

It is conceivable that CRF-BP may modulate CRF-induced behaviors because of its colocalization with CRF and CRF receptors in several brain regions that subserve behavioral function, including the amygdala and the preoptic nucleus (Potter et al., 1992; Kemp et al., 1998). Indeed, some behavioral changes were observed in a-GSU-CRF-BP mice. Specifically, these mice display increased activity in standard behavioral tests and an altered circadian pattern of food intake. Although total food intake was similar to WT mice, feeding behavior was increased during the light phase but diminished during the dark phase (Burrows et al., 1998). Similarly, food intake may have been altered in the mMT-CRF-BP mice as they gained weight more quickly than WT mice (Lovejoy et al., 1998). Taken together, these findings suggest that CRF-BP may modulate certain behaviors associated with CRF/ urocortin although the precise location in the brain of such interaction is unclear.

Was this article helpful?

0 0

Post a comment