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Endocrinology Vol. 143, No. 6 2007-2011
Copyright © 2002 by The Endocrine Society

REPRODUCTION-DEVELOPMENT

Perspective: Genetic and Genomic Approaches in Elucidating Mechanisms of Pituitary Development

Lorin E. Olson and Michael G. Rosenfeld

Biomedical Sciences Graduate Program (L.E.O.), Howard Hughes Medical Institute (M.G.R.), University of California at San Diego, La Jolla, California 92093-0648

Address all correspondence and requests for reprints to: Michael G. Rosenfeld, M.D., University of California at San Diego, Eukaryotic Reg Bio Program, 9500 Gilman Drive, Cellular and Molecular Medicine Room 345, La Jolla, California 92093-0648. E-mail: . mrosenfeld{at}ucsd.edu


   Abstract
Top
 Abstract
Introduction
 The role of repression...
 References
 


   Introduction
Top
 Abstract
 Introduction
The role of repression...
 References
 
Emergence of distinct cell types from a common primordium during pituitary development occurs in response to opposing signaling gradients that induce an overlapping temporal and spatial pattern of transcriptional regulators. Opposing actions of two structurally related DNA-binding transcription factors direct early and late developmental events by sequentially repressing and activating an overlapping set of target genes. Complementary genetic and genomic approaches will now permit a full elucidation of the precise molecular mechanisms that underlie all phases of pituitary organogenesis.

Genetic, molecular biological, and more recently genomic approaches have permitted over the last 25 yr a revealing outline of events that underlie embryogenesis, including the generation of organs containing distinct cell types from common primordia. These investigations have consistently revealed the critical role of spatially expressed signals and gradients of signaling molecules in establishing positional commitment events, based on induction of cohorts of transcription factors that control subsets of genes that specify cell type determination, and subsequently, differentiation. Cell-autonomous commitment is often correlated with establishment of autoregulatory loops of restricted, often cell type-specific transcription factors.

The developing pituitary gland is an instructive model system for investigating the transcriptional control of patterning and cell type specification because its maturation involves a series of distinct stages that generate from a common population of ectodermal progenitors a complex organ composed of six well-defined hormone-producing cell types. The murine pituitary primordium is defined at an intimate point of contact between the neural ectoderm and the oral roof ectoderm on embryonic d 8.5 (E8.5) that marks the first event in development of the pituitary (48). These two embryonic components ultimately produce a three-lobed gland: one part neurohypophysis, the posterior lobe that contains the axonal projections from the hypothalamus, and two parts adenohypophysis, the anterior and intermediate lobes that are composed of the hormone-secreting cell types. Recent studies have demonstrated that patterning of the anterior pituitary emerges through the influence of sequential, opposing signaling gradients, which induce temporally and spatially specific domains of transcription factor expression. The combinatorial distribution of these transcription factors dorsally/ventrally and rostrally/caudally directs cell lineage fate and final differentiation as a gonadotrope (producing FSH and LH), a thyrotrope (producing TSH), a somatotrope (producing GH), a lactotrope (producing PRL), a corticotrope (producing ACTH) or a melanotrope (producing MSH).

Developmental signaling systems have proven to be remarkably conserved throughout evolution, and generally include members of the sonic hedgehog, TGFß/bone morphogenic protein (BMP), fibroblast growth factor, Notch/{delta}, wingless/wnt, specific nuclear receptor, and JAK/STAT families, regulating proliferation and cell determination events, often by opposing actions, although the precise order and role of these factors is distinct in the genesis of different organs. Organ culture and in vivo experiments (18, 49, 50) suggest that multiple external and internal signals are responsible for patterning and proliferation of the pituitary. The presumptive ventral diencephalon provides BMP4, the first known signal required for the initial formation of Rathke’s pouch (1), and subsequently the ventral diencephalon supplies vital proliferative and patterning signals in the form of multiple members of the fibroblast growth factor family (18, 49, 51). Early in pituitary development, a series of factors, including the Six and Pitx homeodomain factors (52, 53, 54, 55, 56) are expressed that are presumably critical for proliferation of the initially committed cells. The Lim homeodomain factors Lhx3/Lhx4 are expressed in the invaginating pouch in response to dorsal BMP4 and Fgf8/10 signals (1), whereas ventral sonic hedgehog and BMP2 signals act in opposition to create a dorsal-ventral pattern of spatially restricted transcription factors with the potential to define all mature cell lineages (49, 50). Sonic hedgehog appears to play roles in both early proliferation and ventral patterning of the pituitary (50), and in vivo experiments suggest that it induces BMP2 expression within the pituitary gland, which is subsequently involved in the induction of the zinc finger protein, GATA2, a modulator of ventral cell-type determination (57). The period of organ expansion and patterning depends on intrinsic BMP2 and Wnt4 signaling, whereas attenuation of BMP2 signaling appears to be required for terminal differentiation (18). As summarized in Table 1Go, a large number of genetic mutations have been found to affect pituitary development; however, the full repertoire of transcription factors, cofactors, receptors and signaling molecules that instruct pituitary development are clearly not known.


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  		Table 1. Transcription factors, signaling molecules, and receptors required for pituitary development

 
With the successful completion of the human genome project and rapid progress in compiling the mouse genome, and with use of subtractive hybridization techniques, there is the opportunity to generate a temporal code of gene activation and repression during the serial events in pituitary development. In a differential display experiment, Douglas and Camper (58) identified 83 transcripts differentially expressed between early, organogenic, and intermediate, proliferative periods in pituitary development. In a second approach, they prepared embryonic cDNA libraries from normal and Prophet of Pit-1 (Prop-1) defective pituitaries and used subtractive hybridization to identify putative Prop-1 target genes that fail to be activated in the dwarf organs (59). Interestingly, their study highlights the potential importance of Wnt signaling in the development of the pituitary gland. Similar methodologies applied to mutants with similar or reciprocal phenotypes (for example, Hesx1/Rpx mutants—see below) should allow the elaboration of the organ’s temporal transcriptome.

We can also expect that a number of types of screens, particularly the use of ENU mutagenesis screens in mice and in nonmurine model organisms, will identify novel genes and pathways that direct the signaling and cell-determination events. Protein-protein interactions, including proteomics techniques, will define the signaling-induced alterations in protein-protein interactions and phosphorylation/methylation/acetylation essential to these events.


   The role of repression and activation in pituitary development
Top
 Abstract
 Introduction
 The role of repression...
References
 
Because there are a number of comprehensive recent reviews of pituitary development (60, 61, 62, 63, 64), we will focus the remainder of this Perspective article on a single issue related to opposing roles of gene activation and repression in pituitary organogenesis (see Fig. 1Go). Indeed, both gene activation and repression events are critically involved in establishing patterns of gene expression during terminal differentiation of hormone-producing cell types (65). An example of this in pituitary development is provided by the paired-like homeodomain proteins, Hesx1/Rpx and Prop-1, two highly related proteins that play sequential roles over critical steps in the pituitary organogenic program. The first, Hesx1/Rpx, is one of several homeodomain proteins that mark the unspecified oral ectoderm before the formation of a rudimentary pituitary placode. By E9.5, Hesx1/Rpx expression becomes restricted to the invaginated segment that contacts the neural epithelium and forms the nascent pituitary, Rathke’s pouch (66). Its expression persists as the pouch detaches from the oral cavity but rapidly disappears after E13.5 when progenitor cells begin to migrate ventrally and express lineage-specific markers. The second paired-like factor, Prop-1, is a tissue-specific homeodomain factor that appears in Rathke’s pouch at E10.5, after the formation of a definitive pouch (22). This timing creates a significant overlap of Prop-1 and Hesx1/Rpx expression between E11.0 and E13.5, followed by a period of exclusive Prop-1 expression that attenuates at E14.5 but remains detectable until birth (7, 22, 23, 67). Thus, a sequential pattern of Hesx1->Hesx1+Prop-1->Prop-1 transpires in the developing adenohypophysis over the period of organ specification, initial morphogenesis, and early differentiation of hormone producing cell types.



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  		Figure 1. Model for the temporal switch of a homeodomain repressor for an activator in mediating early and late events in pituitary organogenesis. Hesx1/Rpx is required for restricting the domain of Fgf8 and Fgf10 expression, as well as for pituitary commitment and growth through appearance of the POMC-expressing lineage on E12. Subsequently, Prop-1 is required for temporal control of proliferation, and for determination of the gonadotropes and the Pit-1 lineage.

 
Both of the two factors can bind cooperatively to the same palindromic DNA site as homo- or heterodimers (22). The Prop-1 homodimer is an efficient activator of transcription; heterodimerization with Hesx1/Rpx blunts this effect. Hesx1 itself is a potent repressor, with at least two independent domains for recruiting corepressor machinery (7). Their intriguing temporal expression pattern predicts an early period of Hesx1-dependent gene repression, a late period of Prop-1- dependent activation, and an intermediate period of antagonism with an outcome dependent, at least in part, on the relative levels of the two factors in the nucleus and the availability of specific corepressors and coactivators.

Heritable Prop-1 mutations in both mice and humans demonstrate that it is required for development of a full complement of hormone-secreting cell types. Studies of Ames dwarf mice that were deficient in somatotropes, lactotropes, and thyrotropes ultimately led to the positional cloning of Prop-1 at the Ames dwarf (df) locus (22, 68, 69). The df allele produces a hypomorphic protein with a serine to proline mutation in the first {alpha} helix of the homeodomain, which impairs but does not abolish DNA binding. Instead of populating the ventral aspect of the pituitary between E12.5-E13.5, most of the cells surrounding the pouch lumen remain in place and expand laterally to produce a dysmorphogenic pouch ectoderm characterized by extensive bifurcation and folding. Therefore, target genes activated by Prop-1 could include those involved in disassociation of progenitors from an undetermined precursor ectoderm, a process that might involve an asymmetric cell division. In the absence of Prop-1, there is essentially no determination of the Pit-1 lineage (somatotropes, lactotropes, and thyrotropes), and Pit-1 is minimally, if at all, activated on E13.5. It remains possible that Pit-1 is be a direct target, but there is no compelling evidence for this assumption. Subtractive hybridization suggests that Prop-1 may play a role in Wnt signaling intrinsic to the developing gland at this time (59).

Prop-1 exerts a similar role governing gonadotrope development, and perhaps even influences corticotrope progenitors. Human PROP1 mutations exist that produce a gene product that is even more severely compromised than the murine df mutation, and these cases are associated with reduced production of FSH and LH (24, 25, 26, 27) and in one case even ACTH insufficiency (28). This supports the idea that Prop-1 functions in the progression or expansion of all, or almost all, anterior pituitary cell types, with some lineages being less sensitive to the hypomorphic df allele, but it could reasonably indicate a role in homeostasis or even a species difference. It should be interesting to analyze mice carrying a null Prop-1 mutation to clarify the extent of its function during murine pituitary development.

During normal pituitary development, as progenitor cells become determined and the lineage-restricted transcription factor Pit-1 appears, certain transcription factors that characterize earlier stages of development are gradually eliminated, including Hesx1/Rpx, P-Frk (18), GATA-3 (60), Pax6 (19), and Brn-4 (22). In the Ames pituitary Hesx1/Rpx expression, as well as Prop-1 and Brn4, extend at least 2 d beyond their normal window, suggesting that timely disappearance of factors expressed early in pituitary ontogeny could be required for the progression of specific cell types (22, 23, 67). With Hesx1/Rpx characterized as a transcriptional repressor (7, 22), it becomes logically possible that an abnormally long period of Hesx1/Rpx-mediated repression could contribute to producing the Ames phenotype in combination with deficiency in the gene activator, Prop-1.

Biochemical and functional assays demonstrate a synergy in the repressive activities of Hesx1/Rpx and mammalian Groucho family members (termed TLEs, for transducin-like enhancer of split). TLE1 is specifically coexpressed with Hesx1/Rpx in Rathke’s pouch, with a similar temporal pattern of mRNA levels at early times. Temporally extending expression of Hesx1/Rpx and TLE1 creates an in vivo antagonism of Prop-1 with loss of the Pit-1 lineage, and frequently results in an Ames-like dysmorphogenesis (7).

Mice lacking Hesx1/Rpx display variable midline defects reminiscent of the human syndrome of septo-optic dysplasia, and genetic screening of affected patients has found HESX1 mutations that produce gene products that fail to bind DNA targets (5, 6). The most severely affected Hesx1/Rpx-null embryos exhibit a complete arrest of pituitary development after the initial induction of Lhx3 on E9.5, with Fgf8 ectopically expressed in the oral ectoderm to mirror its expression in the overlying neural ectoderm. This is potentially significant because transgenic misexpression of Fgf8 in the oral ectoderm well before the initial invagination of Rathke’s pouch produces an identical blockage of pouch formation, and Hesx1/Rpx fails to be expressed in the Lhx3 positive rudiment that does form in the transgenic embryos. The dynamic interplay between boundaries of Hesx1/Rpx and Fgf8/10 expression (7) could suggest a model of reciprocal feedback regulation. Interestingly, a second class of Hesx1/Rpx mutants also occurs, presumably because of redundancy for Hesx1/Rpx function, in which Fgf expression remains restricted to the neural ectoderm but with an abnormally extended rostral boundary causing formation of multiple Rathke’s pouches. This is in keeping with the role of Fgfs in committing oral ectoderm to the Rathke’s pouch fate (1, 9).

Transgenic analysis suggests a functional antagonism between the two paired-like factors in vivo. Temporal misexpression of Prop-1 to the uncommitted oral ectoderm blocks the formation of Rathke’s pouch (7), reminiscent of the severe form of Hesx1/Rpx-null phenotype. Possibly, these Prop-1 transgenic and Hesx1/Rpx-null phenotypes result from failure to repress the same critical target genes. In contrast, extension of the period of Hesx1/TLE1 expression mimics the Ames phenotype, suggesting that, at this stage, Prop-1- dependent genes can fail to be activated due to the antagonistic repressor/corepressor complex. Thus, initial gland development and appearance of the first cell type, POMC-producing cells, requires a repressor/corepressor complex, whereas later appearance and expansion of cell types potentially requires relief of repression and subsequent Prop-1-dependent activation of an overlapping set of gene targets. Later in development, cell type-specific gene activation and repression is observed as part of terminal differentiation, as exemplified by the actions of Pit-1 on the GH promoter (65).

Thus, both activators and repressors underlie the transcriptional code for organ progression, and in some cases, such as those described here, this could even involve reciprocal regulation of overlapping sets of gene targets. Both activators and repressors are linked to proliferation and cell type determination events, and the balance of these opposing regulators, and the expanding number of coregulatory complexes, represent a mechanism of integration of signaling information at the level of gene transcription.


   Acknowledgments
 


   Footnotes
 
Abbreviations: BMP, Bone morphogenic protein; E8.5, embryonic d 8.5; Prop-1, Prophet of Pit-1; TLE, transducin-like enhancer of split.

Received March 5, 2002.

Accepted for publication March 5, 2002.


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