Abstract

The reproductive strategy for avian species that produce a sequence (or clutch) of eggs is dependent upon the maintenance of a small cohort of viable, undifferentiated (prehierarchal) follicles. It is from this cohort that a single follicle is selected on an approximate daily basis to initiate rapid growth and final differentiation before ovulation. This review describes a working model in which follicles within this prehierarchal cohort are maintained in an undifferentiated state by inhibitory cell signaling until the time of selection. Ultimately, follicle selection represents a process in which a single undifferentiated follicle per day is predicted to escape such inhibitory mechanisms to begin rapid growth and final maturation before ovulation. Several processes initiated within the granulosa cell layer at selection are dependent upon G protein-coupled receptors signaling via cyclic adenosine monophosphate (cAMP), and several critical processes are described herein. Finally, reference is made to several practical outcomes that can result from understanding the process of selection, including applications within the poultry industry. Proximal factors and processes that mediate follicle selection can either extend or decrease the length of the laying sequence, and thus directly influence overall egg production. In particular, any aberration that results in the selection of more than one follicle per day will result in decreased egg production. More generally, in wild birds these processes are modified by prevailing environmental conditions and by social interactions to influence clutch size. The elucidation of cellular processes that regulate follicle selection can assist in the development of assisted reproductive technologies for application in threatened and endangered avian species.

INTRODUCTION

The initial growth and development of avian ovarian follicles at puberty, and with each subsequent reproductive season in wild birds, occurs in an orderly and progressive fashion with all stages of follicle development eventually present at the onset of egg production. Specifically, the initiation of lay is preceded by the activation of primordial follicles (initial recruitment) from within the ovarian cortex followed by the organization of primary follicles. This transition occurs via the development of a single inner layer of granulosa cells (GC) plus the incorporation of a multicellular theca layer. In the domestic hen, small (∼1 to 5 mm), slow-growing white follicles incorporate a protein-rich yolk over a period of weeks, and this stage is followed by the uptake of a comparatively more lipid-containing yolk in a smaller cohort of 6 to 8 mm diameter, prehierarchal follicles (Figure 1). Significantly, within this cohort of prehierarchal follicles, the 6 largest are arranged in an orderly fashion, with the weight ranging from ∼150 mg in the sixth largest to ∼230 mg in the largest prehierarchal follicle (unpublished data collected from Hy-Line W-36 white Leghorn hens, 35 to 50 wk old). It is from this prehierarchal cohort that the selection of a single follicle (also referred to as cyclic recruitment) will occur on a daily or near-daily basis for the duration of the laying sequence. Selected follicles immediately begin to take up large amounts of lipid- and xanthophyll-rich yolk via an extensive vasculature, initiate rapid growth and differentiation over a period of days, and thereafter are maintained as an orderly preovulatory hierarchy. In species that produce a comparatively large sequence of eggs (e.g., pheasants, turkeys, chickens), the number of follicles within this preovulatory hierarchy remains relatively constant during the sequence. Accordingly, it is presumed that the ovulation of the largest (F1) preovulatory follicle is accompanied each day by the selection of a prehierarchal follicle for the duration of the sequence, but that no new follicle is selected when an ovulation does not occur (e.g., relative to the pause day). Unfortunately, a mechanism coordinating the process of ovulation with follicle selection is yet unknown. Overall, this pattern of follicle organization, and particularly the maintenance of a viable prehierarchal cohort, is in marked contrast to that in eutherian mammals in which follicle selection each estrous/menstrual cycle is immediately followed by atresia in all subdominant follicles within that growing cohort.

Figure 1.

Unlike the ovary of eutherian mammals, all stages of follicle development exist simultaneously within the reproductively active avian ovary. In the domestic hen, slow-growing, 1- to 5-mm follicles incorporate a protein-rich yolk over a period of weeks (white arrows). The selection of a single follicle into the preovulatory hierarchy (F6 to F1) on a near daily basis occurs from within a cohort of prehierarchal follicles (6- to 8-mm diameter; black arrows). Note the increase in vasculature associated with preovulatory (F1 to F6), compared with prehierarchal, follicles. Perhaps the earliest event marking selection is the acquisition of G protein-coupled receptor signaling specifically within the granulosa layer. This cell signaling initiates several processes critical to the final growth and differentiation of preovulatory follicles, including the rapid uptake of yellow yolk. See text for additional details. Color version available online.

Figure 1.

Unlike the ovary of eutherian mammals, all stages of follicle development exist simultaneously within the reproductively active avian ovary. In the domestic hen, slow-growing, 1- to 5-mm follicles incorporate a protein-rich yolk over a period of weeks (white arrows). The selection of a single follicle into the preovulatory hierarchy (F6 to F1) on a near daily basis occurs from within a cohort of prehierarchal follicles (6- to 8-mm diameter; black arrows). Note the increase in vasculature associated with preovulatory (F1 to F6), compared with prehierarchal, follicles. Perhaps the earliest event marking selection is the acquisition of G protein-coupled receptor signaling specifically within the granulosa layer. This cell signaling initiates several processes critical to the final growth and differentiation of preovulatory follicles, including the rapid uptake of yellow yolk. See text for additional details. Color version available online.

Role of the Granulosa Layer in Follicle Selection

Most investigators have focused primarily on the role of the avian granulosa (versus theca) layer in follicle growth and differentiation, and particularly its many, varied functions at and shortly after the time of follicle selection. This has been justified, in part, by the recognition that within the theca layer neither follicle-stimulating hormone (FSH) receptor (FSHR) mRNA nor luteinizing hormone receptor mRNA (LHR) expression changes significantly during follicle development (Johnson et al., 1996; You et al., 1996). Moreover, cells within the theca layer are responsive to luteinizing hormone and FSH treatment with increased steroid production both prior and subsequent to follicle selection (e.g., Kowalski et al., 1991). By comparison, although cells within the granulosa layer express FSHR mRNA and protein beginning early in follicle development (1 to 2 mm diameter stage), FSH treatment fails to initiate any significant accumulation of cellular cAMP above basal levels until after follicle selection (Tilly et al., 1991; Kim, 2013).

Prior to follicle selection, membrane localized FSHR expression within the GC (Figure 2) is maintained, at least in part, by various growth factors, including bone morphogenetic protein (BMP) 4 (Kim et al., 2013), BMP6 (Ocón-Grove et al., 2012), transforming growth factor β (TGFβ), and activin (Johnson et al., 2004). Significantly, GC cultured in the absence of such supportive growth factors show a significant reduction in FSHR mRNA expression within the first 12 h (Woods and Johnson, 2005). As noted above, the ability of freshly collected GC to accumulate cAMP in response to a 1-h challenge with FSH in the presence of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine is not observed until after follicle selection (e.g., the 9 to 12 mm stage of development). This is not due to the absence of functional adenylyl cyclase activity downstream of the FSHR, as the pharmacologic adenylyl cyclase activator, forskolin, induces a rapid and robust increase in cAMP accumulation (Figure 3). Thus, in the absence of receptor-mediated cAMP, the GC layer remains in an undifferentiated state before selection and this is reflected by undetectable levels of the cAMP-dependent genes, CYP11A1 and CYP17, steroidogenic acute regulatory (STAR) protein, LHR mRNA plus progesterone production (e.g., Li and Johnson, 1993; Johnson and Bridgham, 2001).

Figure 2.

Follicle-stimulating hormone receptor (FSHR) mRNA (C; Woods and Johnson, 2005) and FSHR protein (B) expression relative to stage of follicle development, together with localization of FSHR protein (A; green staining denoted by arrows) to the cell membrane of cultured hen granulosa cells. Nuclear DNA is stained with DAPI (blue). F3 and F1 represent the largest and third largest preovulatory follicle. Color version available online.

Figure 2.

Follicle-stimulating hormone receptor (FSHR) mRNA (C; Woods and Johnson, 2005) and FSHR protein (B) expression relative to stage of follicle development, together with localization of FSHR protein (A; green staining denoted by arrows) to the cell membrane of cultured hen granulosa cells. Nuclear DNA is stained with DAPI (blue). F3 and F1 represent the largest and third largest preovulatory follicle. Color version available online.

Figure 3.

(A) Compared with granulosa cells (GC) from the most recently selected (9 to 12 mm) follicle, GC from 6- to 8-mm prehierarchal follicles fail to accumulate cyclic AMP (cAMP) in response to a 1-h challenge with follicle-stimulating hormone (FSH; 10 ng/mL). (B) By comparison, forskolin induces a robust accumulation of cAMP in prehierarchal follicle GC (Kim, 2013). Data represent the mean and SE; n = 3 to 5 replicate experiments.

Figure 3.

(A) Compared with granulosa cells (GC) from the most recently selected (9 to 12 mm) follicle, GC from 6- to 8-mm prehierarchal follicles fail to accumulate cyclic AMP (cAMP) in response to a 1-h challenge with follicle-stimulating hormone (FSH; 10 ng/mL). (B) By comparison, forskolin induces a robust accumulation of cAMP in prehierarchal follicle GC (Kim, 2013). Data represent the mean and SE; n = 3 to 5 replicate experiments.

Our working model also predicts that before follicle selection GC differentiation is suppressed by active mitogen-activated protein kinase (MAPK) signaling via extracellular signal-regulated kinases (ERK1, ERK2). This proposal is based on studies which show that undifferentiated GC from 6- to 8-mm follicles cultured for 8 h or longer in medium containing only fetal bovine serum (2.5%) begin to acquire FSH responsiveness and initiate FSHR-mediated cAMP production. Significantly, coculture of such GC with one of several epidermal growth factor receptor ligands (e.g., betacellulin, transforming growth factor α, epidermal growth factor) blocks FSH-induced cAMP and prevents the initiation of differentiation (Johnson, 2014). Conversely, GC cultured with a selective MAPK/ERK kinase (MEK) inhibitor (e.g., U0126 or PD98059) promotes FSH-induced expression of differentiation-related genes (e.g., Johnson and Bridgham, 2001).

Granulosa cells collected from prehierarchal follicles also fail to initiate cAMP accumulation in response to the neuropeptide, vasoactive intestinal peptide [vasoactive intestinal peptide (VIP)]. The receptors for both FSHR and VIP [vasoactive intestinal peptide receptor 1 (VPAC1) and vasoactive intestinal peptide receptor 2 (VPAC2)] represent members of the G protein-coupled receptor (GPCR) family of receptors that signal via cAMP, and receptor signaling by such GPCR is known to be negatively regulated by β-arrestin (Troispoux et al., 1999). Recent studies using hen ovarian GC have established that before follicle selection both the FSHR and VPAC1/2 are desensitized via a β-arrestin-mediated process (Kim, 2013). We predict that the inhibitory effects of MAPK/ERK signaling and FSHR/VPAC desensitization are mediated via β-arrestin. Accordingly, it is also predicted that follicle selection occurs, at least in part, as a result of the removal of such inhibitory signaling. Interestingly, acute inhibitory effects of MAPK/ERK activation have also been reported in GC from the F1 and F2 preovulatory follicles. In these studies, short-term treatment with epidermal growth factor (EGF) inhibited LH-induced progesterone synthesis at sites both prior and subsequent to cAMP production (Pulley and Marrone, 1986). It would be of interest to assess whether such reported actions of EGF before cAMP formation are mediated via cellular mechanisms similar to prehierarchal follicles.

Nevertheless, several fundamental concepts related to the working model presented remain to be elucidated. First, anti-Mullerian hormone (AMH) has also been implicated in regulating FSH responsiveness in developing hen follicles (Johnson, 2012), yet it is unclear how (or if) the actions of AMH are related to this proposed model. Second, it remains to be determined how FSHR signaling via cAMP is initiated in GC precisely at follicle selection. Finally, it will be important to determine how selection into the preovulatory hierarchy is normally restricted to a single follicle per ovulatory cycle. Significantly, this latter unanswered question also pertains to follicle selection in monovulatory mammals (e.g., humans, cattle, horses).

Preovulatory Follicle Growth and Differentiation

Follicle selection initiates both the differentiation of GC and the rapid growth phase in preovulatory follicles, and many of the processes involved are initiated specifically within the GC layer by GPCR signaling via cAMP. Accordingly, each of the processes noted below are dependent upon cAMP signaling immediately subsequent to follicle selection. As noted above, one of the best-characterized processes initiated by FSHR and VPAC signaling in GC is the upregulation of STAR, CYP11A1, and CYP17 expression, and the onset of steroidogenesis. This is followed by the well-documented initiation of LHR mRNA expression and LH-induced progesterone, and to a lesser extent androgen, production by preovulatory follicle GC.

Whereas under normal conditions follicle atresia can occur at any stage during development, follicles within the preovulatory hierarchy are generally resistant to becoming atretic unless, for instance, the female is perturbed (e.g., by withdrawal of food or water) or until the beginning of incubation. Preovulatory follicle viability is largely attributed to the acquired resistance of the GC layer to apoptosis (reviewed in Johnson, 2003). Specifically, the transition from a prehierarchal follicle to the preovulatory stage of development is associated with dramatically increased resistance to apoptosis and increased cell proliferation in cultured hen GC. The resistance to apoptosis is mediated by products of several cAMP-induced anti-apoptotic genes, including inhibitor of apoptosis protein, B-cell lymphoma-extra large (BCL-X), and B-cell lymphoma-2 (BCL-2).

Enhanced FSH-induced inhibitor of differentiation 2 (ID2) mRNA expression within the GC layer also occurs coincident with selection. Expression of ID2 protein has been associated with a differentiated GC phenotype, as the knock-down of ID2 in actively differentiating GC results in a reduction of FSHR and LHR expression, FSH-induced STAR and CYP11A1 expression, and progesterone production (Johnson et al., 2008).

One of the most dramatic changes associated with follicle selection is the rapid increase in follicle size due to yolk uptake. In the domestic hen, an increase in size from approximately 0.03 g just before selection to some 16 g at ovulation is accomplished by a concurrent increase in vasculature (Figure 1) and blood flow (Scanes et al., 1982). Notably, there also occurs a significant increase in vascular endothelial growth factor (VEGF) expression, specifically within the GC layer from the 9 to 12 mm stage of development compared with the 6 to 8 mm prehierarchal stage, and this increase in VEGF mRNA and protein expression is promoted by GPCR/cAMP-induced signaling (Kim, 2013). Prior to selection, tight junctions are proposed to represent a limitation to the paracellular transport of yolk to the oocyte (Schuster et al., 2004). At selection and coincident with enhanced blood vasculature, there occurs a dramatically increased rate of vitellogenin and very low density lipoprotein uptake by the oocyte. It is predicted that this abrupt increase in transport results, at least in part, from a cAMP-mediated reduction in occludin, as previously described for Sertoli cell tight junctions (Lui and Lee, 2005). From this point, large amounts of yolk are transported across the perivitelline membrane and into the oocyte via the LR8 receptor (Bujo et al., 1994).

There is now considerable evidence that circadian clocks function within most if not all peripheral tissues and organ systems, including the ovary (Nakao et al., 2007; Tischkau et al., 2011). A circadian clock consists of an oscillating loop of clock proteins that act to regulate rhythms of target gene expression. Heterodimers consisting of BMAL and CLOCK drive expression of PERIOD and CRYPTOCHROME, which in turn negatively feedback to inhibit BMAL/CLOCK expression. In both the quail and chicken ovaries, clock protein rhythmicity is evident within the GC layer of preovulatory follicles. Moreover, within the largest (F1) preovulatory follicle such rhythmicity is reported to assist in the timing of ovulation (Nakao et al., 2007; Tischkau et al., 2011). By comparison, clock gene rhythmicity is absent from the GC layer of prehierarchal follicles (Nakao et al., 2007; Tischkau et al., 2011; Kim, 2013). Significantly, BMAL expression in GC is induced by treatment with VIP, but only in GC from selected (preovulatory) follicles (Kim, 2013). These preliminary findings suggest that the onset of GPCR signaling via cAMP at the time of follicle selection may help initiate and phase a rhythmic expression of clock genes within the GC layer of preovulatory follicles.

In summary, our recent studies have focused on defining cellular mechanisms that regulate the process of follicle selection and mediate final growth and differentiation (Figure 4) in avian species using the domestic hen as a model system. This process has yet to be adequately defined in any bird or monovulatory mammal, yet has significant implications toward maximizing egg production in domesticated species of birds, as well as in determining clutch size in wild birds and overall fertility in mammals. Several fundamental questions related to the avian model proposed herein remain to be elucidated. In particular, does follicle selection always occur from the largest follicle within the prehierarchal cohort? Is follicle selection mechanistically linked to ovulation? How is FSH- and VIP-induced signaling via cAMP initiated within the GC layer precisely at follicle selection? Moreover, how is selection into the preovulatory hierarchy normally restricted to a single follicle per ovulatory cycle? Finally, although it is predicted that the cellular mechanisms mediating the process of follicle selection in birds (Sauropsid lineage) versus monovulatory mammals (Synapid lineage; e.g., humans, cattle, horses) have evolved independently and are unique, it is evident that the final growth and differentiation of the selected follicle is highly dependent upon GPCR signaling via cAMP in both mammals (Conti, 2002) and birds.

Figure 4.

At selection, the G protein-coupled receptor (GPCR), follicle-stimulating hormone (FSH) receptor (FSHR), and VPAC1/2 acquire the capacity for cell signaling via cyclic AMP specifically within the granulosa cell (GC) layer. This signaling initiates several processes required for the growth, survival, and maturation of preovulatory follicles, including cell proliferation; enhanced expression of inhibitor of differentiation 2 (ID2) expression; the initial expression of genes required for steroidogenesis [steroidogenic acute regulatory (STAR) and cAMP-dependent genes (CYP11A1 and CYP17)]; enhanced expression of anti-apoptotic proteins (e.g., inhibitor of apoptosis protein, BCL-X, BCL-2); upregulation of the clock protein, BMAL; increased expression of vascular endothelial growth factor (VEGF) to promote growth of the vasculature and uptake of yolk; and initiation of luteinizing hormone receptor (LHR) expression. AC, Adenylyl cyclase; Gαs, G stimulatory alpha subunit protein. See text for additional details. Color version available online.

Figure 4.

At selection, the G protein-coupled receptor (GPCR), follicle-stimulating hormone (FSH) receptor (FSHR), and VPAC1/2 acquire the capacity for cell signaling via cyclic AMP specifically within the granulosa cell (GC) layer. This signaling initiates several processes required for the growth, survival, and maturation of preovulatory follicles, including cell proliferation; enhanced expression of inhibitor of differentiation 2 (ID2) expression; the initial expression of genes required for steroidogenesis [steroidogenic acute regulatory (STAR) and cAMP-dependent genes (CYP11A1 and CYP17)]; enhanced expression of anti-apoptotic proteins (e.g., inhibitor of apoptosis protein, BCL-X, BCL-2); upregulation of the clock protein, BMAL; increased expression of vascular endothelial growth factor (VEGF) to promote growth of the vasculature and uptake of yolk; and initiation of luteinizing hormone receptor (LHR) expression. AC, Adenylyl cyclase; Gαs, G stimulatory alpha subunit protein. See text for additional details. Color version available online.

This review is written in honor and remembrance of Ari van Tienhoven, whose mentorship, friendship and ever-present encouragement continue to serve as an inspiration. I thank Dongwon Kim (Department of Dermatology Johns Hopkins School of Medicine) for contributions to several portions of the work discussed. Support for this work was provided by NSF IOS-1354713 and the Walther H. Ott Endowment to ALJ.

1
Presented as part of the Symposium: Avian Reproduction: Foundational Advances and Practical Applications at the Poultry Science Association's annual meeting in Corpus Christi, Texas, July 14 to 17, 2014.

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