A FoxL in the Smad house: activin regulation of FSH

Abstract

Follicle-stimulating hormone (FSH), produced by pituitary gonadotrope cells, is required for maturation of ovarian follicles. The FSHbeta subunit is the limiting factor for production of mature hormone and provides biological specificity. Activin dramatically induces FSHbeta transcription and the secondary rise in FSH, important for follicular development, is dependent on this induction. Thus, regulation of FSHbeta levels by activin is crucial for female reproductive fitness. This review discusses activin signaling pathways, transcription factors and FSHbeta promoter elements required for activin responsiveness. Because FoxL2, a forkhead transcription factor, was recently shown to be instrumental in relaying activin signaling to the FSHbeta promoter, we focus in this paper on its role and the inter-relatedness of several key players in activin responsiveness on the FSHbeta promoter.

Figure 1

Activin signaling regulates transcription of the FSHβ gene. Activin signaling, via ActRIIA/B and ALK4/7 receptors, results in the phosphorylation of Smad2 and 3, which then dimerize with the common Smad4 and translocate into the nucleus of the cell. Activated Smad3, and potentially Smad2, regulate transcription of FSHβ and other specific target genes. The inhibitory Smad7 prevents the phosphorylation of Smad3. Activin signaling also results in activation of the p38 MAPK signaling pathway, potentially via TAK1, however, it is still unclear how p38 relays activin signaling to the FSHβ promoter.

Figure 2

FSHβ promoter elements important for activin responsiveness. Numerous studies have identified elements in the mouse, rat, sheep, pig, and human FSHβ promoters that are critical for activin induction. Since all of the elements have been examined in the murine promoter, it was used as a basis for comparison. The number above each element corresponds to the number in the original publication, while the number next to the sequence indicates the position of the 5′ nucleotide that is presented. Mutated residues are underlined and the relevant publications are indicated in brackets. The –350 site binds FoxL2 in the murine but not the human promoter; other species have not yet been examined. The –267 SBE is present only in the rodent promoters. The murine –208 and corresponding human –223 FoxL2 sites play a critical role in activin responsiveness; other species have not yet been examined. The binding elements in the more proximal region of the FSHβ promoter are not as clearly defined. The forkhead (FH) consensus is aligned beneath the corresponding sites in this region to help identify potential FoxL2 binding elements.

Figure 3

Different mechanisms for modulation of activin responsiveness on the FSHβ promoter. (a) Smad3 and 4 bind directly to the FSHβ promoter. Direct Smad binding has been demonstrated on rodent FSHβ promoters via a consensus SBE. (b) Smad3/4 can also interact with other transcription factors such as Pbx/Prep and be recruited to the FSHβ promoter via tethering. Although Ptx and FoxL2 can interact with Smads, it remains to be determined whether they tether Smads to the FSHβ promoter. (c) FoxL2 binds directly to the FSHβ promoter in several mammalian species, and FoxL2 binding elements are critical for activin induction. It is unknown whether FoxL2 is regulated directly by activin signaling pathways and if FoxL2 acts in a Smad-independent manner in the pituitary, as in the ovary. (d) Runx proteins diminish induction of the FSHβ gene, potentially through interactions with Smad3 or other regulators of activin induction such as FoxL2.