Endocrinology Vol. 148, No. 5 1943-1945
Copyright © 2007 by The Endocrine Society
Redefining Ancestral Relationships in Pituitary Cell Genealogy
Timothy Wells
School of Biosciences Cardiff University Cardiff CF10 3US United Kingdom
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Introduction
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The most productive approach for tracing the ancestry of secretory cells in the adenohypophysis has been the analysis of the pituitary phenotype of mice with either spontaneous or engineered genetic mutations. These studies have revealed that the appearance of the full pantheon of adenohypophysial secretory cells during embryonic development is dependent upon the correct spatiotemporal expression of an array of transcription factors. And although less well characterized, the subsequent postnatal expansion of these specific cell types appears to be regulated by an intricate balance of proliferative and antiproliferative signals (reviewed in Refs. 1 and 2).
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Relationships in the Somatotroph/Lactotroph Lineage
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The GH-secreting somatotrophs and the prolactin (PRL)-secreting lactotrophs are intimately related developmentally. In the majority of rodent models of GH-deficient dwarfism, the populations of both of these cell types are reduced in parallel, indicating that they are either part of a common lineage or share a common parentage. Commitment to the somatotroph/lactotroph lineage is dependent upon the sequential expression of the Prophet of Pit-1 (Prop-1) (3) and the pituitary transcription factor, Pit-1 (4); missense mutations in either Prop-1 (3, 5) or Pit-1 (4, 5, 6) leading to a failure in the appearance of somatotrophs, lactotrophs, and a subset of thyrotrophs. The somatotrophs and lactotrophs are thought to arise from a common bihormonal progenitor, the mammosomatotroph (7, 8), with subsequent postnatal expansion of the monohormonal cells being regulated by an incompletely understood set of signals. The extant model of this process is summarized in Fig. 1
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FIG. 1. The currently accepted model of the development of the somatotroph/lactotroph lineage. The development of the bihormonal mammosomatotrophs (MS) from a nominal progenitor (PG) represents an obligatory intermediate step in the development of the somatotrophs (S) and the types II (Lii) and I lactotrophs (Li) and the interconversion between these monohormonal cells. The transcription factors Prop-1 and Pit-1 are required for the appearance of the somatotroph/lactotroph lineage and a subset of thyrotrophs in the intermediate caudomedial field (Tic), whereas a subset of somatotroph progenitors (Sp) arises independently of the MSs. The postnatal expansion of the monohormonal cells is regulated by the combined action of GHRH, TGF , nerve growth factor (NGF), estrogen (E2), and dopamine. The stronger individual relationships are indicated by heavier line weights, with dashed lines showing less well-established relationships.
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However, progress in defining the exact genealogical relationship between these cells types has been hampered by our inability to gain temporal resolution within the somatotroph/lactotroph lineage. Such questions as "is the bihormonal mammosomatotroph an obligatory precursor for somatotrophs and lactotrophs?" or "do the lactotrophs arise from a previous somatotrophic incarnation?" have been difficult to address directly. In an elegant study in this issue of Endocrinology (9), Kineman and colleagues have developed a novel approach to circumvent this temporal hiatus, yielding surprising results that question the model outlined above.
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The rGHp-Cre Recombinase Transgenic Mouse
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Luque et al. (9) have developed a transgenic mouse in which Cre recombinase is expressed in GH-positive cells under the control of the rat GH promoter. When crossed with Z/AP mice (10), the presence of Cre recombinase induced recombination of a loxP flanked DNA sequence, leading to the expression of human placental alkaline phosphatase (hPLAP). In this way, any cell in the somatotroph/lactotroph lineage that had once expressed GH (and therefore Cre recombinase) was identified in perpetuity by the continuing presence of hPLAP.
The efficacy of this approach can be seen from the observation that all but a small minority (
2% of the total somatotroph population) of GH-positive cells were immunopositive for hPLAP and that none of the cells that were immunopositive for hPLAP-expressed ACTH, TSH, or LH. These results not only confirm the efficiency of Cre-mediated recombination of loxP-modified alleles, but demonstrate that the pituitary basophils had not previously expressed GH.
Further analysis of the rGHp-Cre recombinase transgenic mice revealed that a small population of pituitary cells immunopositive for hPLAP (3–5%) did not currently express GH. Because these cells were included in a dual GH/PRL immunocytochemical approach, they were assumed to equate to a subpopulation of lactotrophs. These GH-negative, PRL/hPLAP-positive cells have arisen from the somatotroph/mammosomatotroph lineage and were previously unobservable. Thus, the rGHp-Cre recombinase approach has enabled resolution of this temporal relationship.
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Redrawing the Family Tree
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However, the most striking observation in this study is that only a small proportion of the total number of lactotrophs (10%) were found to coexpress hPLAP. This clearly implies that the majority of lactotrophs arise from a GH-independent ancestry, i.e. independent of both the somatotrophs and the mammosomatotrophs. These data require that the previously accepted model of cell specification in the somatotroph/lactotroph lineage be redrawn. Two alternative models suggest themselves (Fig. 2).
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FIG. 2. Alternative models of the development of the somatotroph/lactotroph lineage. In option A the majority of lactotrophs arise from the direct differentiation pathway [possibly including a mammosomatotroph (MS)-independent lactotroph progenitor (Lp)], with a subset being derived from the bihormonal MSs. In option B the majority of somatotrophs (S) arise through the lactotroph lineage and a minority of lactotrophs arise through the S/MS lineage. PG, Nominal progenitor; Tic, thyrotrophs in the intermediate caudomedial field; Lii, type II lactotrophs; Li, type I lactotrophs. The stronger individual relationships are indicated by heavier line weights, with dashed lines showing less well-established relationships.
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Firstly, taking a conservative approach, somatotroph and lactotroph progenitors, together with the mammosomatotrophs (and the intermediate caudomedial thyrotrophs) are direct descendents of a Prop-1/Pit-1-dependent progenitor (Fig. 2
, option A). In this option the majority of lactotrophs arise either directly, or through a lactotroph progenitor, whereas a minority arise from the differentiation of mammosomatotrophs, possibly from a prior somatotroph incarnation.
Secondly, given that a reduction in somatotroph population is usually accompanied by a reduction in lactotrophs, this study clearly raises the simpler, though somewhat more radical, proposition that the lactotrophs are obligatory precursors for the somatotrophs (via the mammosomatotrophs) (Fig. 2, option B). In this scenario, the majority of lactotrophs are direct descendents of the nominal progenitor cell, with a minority arising through the somatotroph lineage. Conversely, the somatotrophs arise primarily through the lactotroph lineage, with a minority descending from the somatotroph progenitors.
Either of these options could account for the findings of the present study. In addition, both scenarios could also account for the reduction in lactotrophs in the rGH-DT-A transgenic mice (11), as the continual destruction of somatotrophs may induce the conversion of more lactotrophs to somatotrophs. However, the more radical model (option B) does not readily account for the observation that the GH-secreting cells not only appear earlier than the earliest PRL-secreting cells, but that the majority of early PRL-secreting cells cosecrete GH (12).
The essential difference between these two models of pituitary ancestry is the potential role of the mammosomatotroph as an obligatory precursor for both the somatotroph and lactotroph lineages and as a direct descendent from the Prop-1/Pit-1-dependent progenitor. To determine whether the majority of somatotrophs previously expressed PRL (either alone or in combination with GH) the reverse experiment is necessary viz. expression of Cre-recombinase under the control of the PRL promoter. This would establish whether the production of the majority of monohormonal somatotrophs and lactotrophs is truly independent.
The novel rGHp-Cre model clearly has further physiological utility to answer such questions as, "what proportion of the additional lactotrophs that appear during pregnancy arise from cells that previously expressed GH, either alone or in combination with PRL?" But for the present, the authors should be commended for developing this novel strategy and casting doubt on the extant model of pituitary cell ancestry. Surely questioning the validity of accepted models is of the very essence of scientific enquiry?
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Footnotes
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Address for correspondence: Dr. Tim Wells, School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3US, United Kingdom. E-mail: wellst{at}cardiff.ac.uk.
Abbreviations: hPLAP, Human placental alkaline phosphatase; PRL, prolactin; Prop-1, Prophet of Pit-1.
Received February 15, 2007.
Accepted for publication February 16, 2007.
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References
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