All Hormone-Producing Cell Types of the Pituitary Intermediate and Anterior Lobes Derive From Prop1-Expressing Progenitors

Abstract Mutations in PROP1, the most common known cause of combined pituitary hormone deficiency in humans, can result in the progressive loss of all hormones of the pituitary anterior lobe. In mice, Prop1 mutations result in the failure to initiate transcription of Pou1f1 (also known as Pit1) and lack somatotropins, lactotropins, and thyrotropins. The basis for this species difference is unknown. We hypothesized that Prop1 is expressed in a progenitor cell that can develop into all anterior lobe cell types, and not just the somatotropes, thyrotropes, and lactotropes, which are collectively known as the PIT1 lineage. To test this idea, we produced a transgenic Prop1-cre mouse line and conducted lineage-tracing experiments of Prop1-expressing cells. The results reveal that all hormone-secreting cell types of both the anterior and intermediate lobes are descended from Prop1-expressing progenitors. The Prop1-cre mice also provide a valuable genetic reagent with a unique spatial and temporal expression for generating tissue-specific gene rearrangements early in pituitary gland development. We also determined that the minimal essential sequences for reliable Prop1 expression lie within 10 kilobases of the mouse gene and demonstrated that human PROP1 can substitute functionally for mouse Prop1. These studies enhance our understanding of the pathophysiology of disease in patients with PROP1 mutations.

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Persistent Expression of Notch2 Delays Gonadotrope Differentiation

Molecular Endocrinology ◽

10.1210/me.2005-0394 ◽

2006 ◽

Vol 20 (11) ◽

pp. 2898-2908 ◽

Cited By ~ 48

Author(s):

Lori T. Raetzman ◽

Bayly S. Wheeler ◽

Shelley A. Ross ◽

Paul Q. Thomas ◽

Sally A. Camper

Keyword(s):

Cell Differentiation ◽

Pituitary Gland ◽

Progenitor Cell ◽

Anterior Lobe ◽

Temporal Expression ◽

Cell Specification ◽

Pituitary Development ◽

Normal Pituitary Gland ◽

Gland Development ◽

Selection Of

Abstract Normal pituitary gland development requires coordination between maintenance of progenitor cell pools and selection of progenitors for differentiation. The spatial and temporal expression of Notch2 during pituitary development suggested that it could control progenitor cell differentiation in the pituitary. Consistent with this idea, Notch2 is not expressed in Prop1 mutants, and anterior pituitary progenitors in Prop1 mutants appear to be unable to transition from proliferation to differentiation properly, resulting in anterior lobe failed cell specification and evolving hypoplasia. To test the function of Notch2 directly, we used the αGSU subunit promoter to express activated NOTCH2 persistently in pre-gonadotropes and pre-thyrotropes of transgenic mice. At birth, there is a small reduction in the population of fully differentiated thyrotropes and almost no fully differentiated gonadotropes. The temporal and spatial expression of Hey1 suggests that it could be a mediator of this effect. Gonadotropes complete their differentiation program eventually, although expression of LH and FSH is mutually exclusive with NOTCH2 transgene expression. This demonstrates that activated Notch2 is sufficient to delay gonadotrope differentiation, and it supports the hypothesis that Notch2 regulates progenitor cell differentiation in the pituitary gland.

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A novel mutation of the <i>GLI2</i> gene associated with body weight in bovine (<i>Bos taurus</i>) (Brief Report)

Archives Animal Breeding ◽

10.5194/aab-52-334-2009 ◽

2009 ◽

Vol 52 (3) ◽

pp. 334-336

Author(s):

X. Wang ◽

X. Lan ◽

X. Lai ◽

K. Wang ◽

H. Yu ◽

...

Keyword(s):

Bos Taurus ◽

Novel Mutation ◽

Cell Types ◽

Hormone Deficiency ◽

Pituitary Hormone ◽

Coding Region ◽

Spinal Cord Development ◽

Transcription Factor Genes ◽

Gland Development ◽

Brain And Spinal Cord

Abstract. During pituitary gland development, the actions of transcription factors control the development of the hormone-producing cell types. Defects in transcription factor genes, including PIT1/POU1F1, PROP1, GLI2, HESX1, LHX3, and LHX4, are associated with combined pituitary hormone deficiency (CPHD) (SAVAGE et al. 2007). Removal of the mouse GLI2 gene by targeted disruption leads to an embryonic lethal phenotype with defects in early brain and spinal cord development, which include absence of the floor plate (MATISE et al. 1998). At present, no polymorphisms of GLI2 gene have been reported in bovine. In the present paper, partial 5’ flanking region, coding region and partially introns of GLI2 were screened to detect the SNPs in Chinese cattle breeds.

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Lhx4 and Prop1 are required for cell survival and expansion of the pituitary primordia

Development ◽

10.1242/dev.129.18.4229 ◽

2002 ◽

Vol 129 (18) ◽

pp. 4229-4239 ◽

Cited By ~ 1

Author(s):

Lori T. Raetzman ◽

Robert Ward ◽

Sally A. Camper

Keyword(s):

Cell Survival ◽

Anterior Pituitary ◽

Molecular Genetic ◽

Cell Types ◽

Hormone Deficiency ◽

Pituitary Hormone ◽

Pituitary Cells ◽

Temporal Shift ◽

Pituitary Development ◽

Show Evidence

Deficiencies in the homeobox transcription factors LHX4 and PROP1 cause pituitary hormone deficiency in both humans and mice. Lhx4 and Prop1 mutants exhibit severe anterior pituitary hypoplasia resulting from limited differentiation and expansion of most specialized cell types. Little is known about the mechanism through which these genes promote pituitary development. In this study we determined that the hypoplasia in Lhx4 mutants results from increased cell death and that the reduced differentiation is attributable to a temporal shift in Lhx3 activation. In contrast, Prop1 mutants exhibit normal cell proliferation and cell survival but show evidence of defective dorsal-ventral patterning. Molecular genetic analyses reveal that Lhx4 and Prop1 have overlapping functions in early pituitary development. Double mutants exhibit delayed corticotrope specification and complete failure of all other anterior pituitary cell types to differentiate. Thus, Lhx4 and Prop1 have critical, but mechanistically different roles in specification and expansion of specialized anterior pituitary cells.

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Reprogramming of Sertoli cells to fetal-like Leydig cells by Wt1 ablation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1422371112 ◽

2015 ◽

Vol 112 (13) ◽

pp. 4003-4008 ◽

Cited By ~ 50

Author(s):

Lianjun Zhang ◽

Min Chen ◽

Qing Wen ◽

Yaqiong Li ◽

Yaqing Wang ◽

...

Keyword(s):

Gene Expression ◽

Somatic Cell ◽

Progenitor Cells ◽

Sertoli Cell ◽

Sertoli Cells ◽

Leydig Cells ◽

Gonad Development ◽

Cell Types ◽

Lineage Tracing ◽

Specific Gene

Sertoli and Leydig cells, the two major somatic cell types in the testis, have different morphologies and functions. Both are essential for gonad development and spermatogenesis. However, whether these cells are derived from the same progenitor cells and the mechanism regulating the differentiation between these two cell types during gonad development remains unclear. A previous study showed that overactivation of Ctnnb1 (cadherin-associated protein, beta 1) in Sertoli cells resulted in Sertoli cell tumors. Surprisingly, in the present study, we found that simultaneous deletion of Wilms’ Tumor Gene 1 (Wt1) and overactivation of Ctnnb1 in Sertoli cells led to Leydig cell-like tumor development. Lineage tracing experiments revealed that the Leydig-like tumor cells were derived from Sertoli cells. Further studies confirmed that Wt1 is required for the maintenance of the Sertoli cell lineage and that deletion of Wt1 resulted in the reprogramming of Sertoli cells to Leydig cells. Consistent with this interpretation, overexpression of Wt1 in Leydig cells led to the up-regulation of Sertoli cell-specific gene expression and the down-regulation of steroidogenic gene expression. These results demonstrate that the distinction between Sertoli cells and Leydig cells is regulated by Wt1, implying that these two cell types most likely originate from the same progenitor cells. This study thus provides a novel concept for somatic cell fate determination in testis development that may also represent an etiology of male infertility in human patients.

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From Cell States to Cell Fates: How Cell Proliferation and Neuronal Differentiation Are Coordinated During Embryonic Development

Frontiers in Neuroscience ◽

10.3389/fnins.2021.781160 ◽

2022 ◽

Vol 15 ◽

Author(s):

Carla Belmonte-Mateos ◽

Cristina Pujades

Keyword(s):

Progenitor Cells ◽

Progenitor Cell ◽

New Technologies ◽

Cell Lineage ◽

Cell Types ◽

Lineage Tracing ◽

Vertebrate Brain ◽

Proliferation And Differentiation ◽

Cell Diversity ◽

The Right

The central nervous system (CNS) exhibits an extraordinary diversity of neurons, with the right cell types and proportions at the appropriate sites. Thus, to produce brains with specific size and cell composition, the rates of proliferation and differentiation must be tightly coordinated and balanced during development. Early on, proliferation dominates; later on, the growth rate almost ceases as more cells differentiate and exit the cell cycle. Generation of cell diversity and morphogenesis takes place concomitantly. In the vertebrate brain, this results in dramatic changes in the position of progenitor cells and their neuronal derivatives, whereas in the spinal cord morphogenetic changes are not so important because the structure mainly grows by increasing its volume. Morphogenesis is under control of specific genetic programs that coordinately unfold over time; however, little is known about how they operate and impact in the pools of progenitor cells in the CNS. Thus, the spatiotemporal coordination of these processes is fundamental for generating functional neuronal networks. Some key aims in developmental neurobiology are to determine how cell diversity arises from pluripotent progenitor cells, and how the progenitor potential changes upon time. In this review, we will share our view on how the advance of new technologies provides novel data that challenge some of the current hypothesis. We will cover some of the latest studies on cell lineage tracing and clonal analyses addressing the role of distinct progenitor cell division modes in balancing the rate of proliferation and differentiation during brain morphogenesis. We will discuss different hypothesis proposed to explain how progenitor cell diversity is generated and how they challenged prevailing concepts and raised new questions.

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A Non-stop identity complex (NIC) supervises enterocyte identity and protects from pre-mature aging

10.1101/2020.08.23.263095 ◽

2020 ◽

Author(s):

Neta Erez ◽

Lena Israitel ◽

Eliya Bitman-Lotan ◽

Wing Hing Wong ◽

Gal Raz ◽

...

Keyword(s):

Progenitor Cell ◽

Large Scale ◽

Gene Expression Signature ◽

Chromatin Accessibility ◽

Lineage Tracing ◽

Premature Aging ◽

Specific Gene ◽

Wild Type ◽

Tissue Integrity ◽

Differentiated Cells

SummaryA hallmark of aging is the inability of differentiated cells to maintain their identity. In the aged Drosophila midgut differentiated enterocytes (ECs) lose their identity, and the integrity of the midgut tissue and its homeostasis are impaired. To discover regulators of EC identity relevant to aging we performed an RNAi screen targeting 453 ubiquitin-related genes in fully differentiated ECs. Seventeen genes were identified, including the de-ubiquitinase Non-stop (Not/dUSP22; CG4166). Acute loss of Non-stop in young ECs phenotypically resembled aged ECs. Lineage tracing experiments established that Non-stop-deficient young ECs as well as wild-type aged ECs are no longer differentiated. Aging or acute loss of Non-stop also resulted in progenitor cell hyperproliferation and mis-differentiation, loss of gut integrity, and reduced organismal survival. Proteomic analysis unveiled that Non-stop maintains identity as part of a Non-stop identity complex (NIC) that contains E(y)2, Sgf11, Cp190, (Mod) mdg4, and Nup98. Transcriptionally, Non-stop ensured chromatin accessibility at EC genes, maintained an EC-specific gene expression signature, and silenced non-EC-relevant transcriptional programs. Within the NIC, Non-stop was required for stabilizing of NIC subunits. Upon aging, the levels of Non-stop and NIC subunits declined, and the large-scale organization of the nucleus was distorted. Maintaining youthful levels of Non-stop in wildtype aged ECs safeguarded the protein level of NIC subunits, restored the large-scale organization of the differentiated nucleus, and suppressed aging phenotypes and tissue integrity. Thus, the isopeptidase Non-stop, and NIC, supervise EC identity and protects from premature aging.

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Epithelial Cell Lineage and Signaling in Murine Salivary Glands

Journal of Dental Research ◽

10.1177/0022034519864592 ◽

2019 ◽

Vol 98 (11) ◽

pp. 1186-1194 ◽

Cited By ~ 4

Author(s):

M.H. Aure ◽

J.M. Symonds ◽

J.W. Mays ◽

M.P. Hoffman

Keyword(s):

Salivary Gland ◽

Epithelial Cells ◽

Cell Fate ◽

Cell Lineage ◽

Cell Types ◽

Lineage Tracing ◽

Genetic Lineage ◽

Recent Advances ◽

Epithelial Development ◽

Gland Development

Maintaining salivary gland function is critical for oral health. Loss of saliva is a common side effect of therapeutic irradiation for head and neck cancer or autoimmune diseases such as Sjögren’s syndrome. There is no curative treatment, and current strategies proposed for functional regeneration include gene therapy to reengineer surviving salivary gland tissue, cell-based transplant therapy, use of bioengineered glands, and development of drugs/biologics to stimulate in vivo regeneration or increase secretion. Understanding the genetic and cellular mechanisms required for development and homeostasis of adult glands is essential to the success of these proposed treatments. Recent advances in genetic lineage tracing provide insight into epithelial lineage relationships during murine salivary gland development. During early fetal gland development, epithelial cells expressing keratin 14 (K14) Sox2, Sox9, Sox10, and Trp63 give rise to all adult epithelium, but as development proceeds, lineage restriction occurs, resulting in separate lineages of myoepithelial, ductal, and acinar cells in postnatal glands. Several niche signals have been identified that regulate epithelial development and lineage restriction. Fibroblast growth factor signaling is essential for gland development, and other important factors that influence epithelial patterning and maturation include the Wnt, Hedgehog, retinoic acid, and Hippo signaling pathways. In addition, other cell types in the local microenvironment, such as endothelial and neuronal cells, can influence epithelial development. Emerging evidence also suggests that specific epithelial cells will respond to different types of salivary gland damage, depending on the cause and severity of damage and the resulting damaged microenvironment. Understanding how regeneration occurs and which cell types are affected, as well as which signaling factors drive cell lineage decisions, provides specific targets to manipulate cell fate and improve regeneration. Taken together, these recent advances in understanding cell lineages and the signaling factors that drive cell fate changes provide a guide to develop novel regenerative treatments.

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Hypothalamic and pituitary development: novel insights into the aetiology

Acta Endocrinologica ◽

10.1530/eje-07-0156 ◽

2007 ◽

Vol 157 (suppl_1) ◽

pp. S3-S14 ◽

Cited By ~ 54

Author(s):

Daniel Kelberman ◽

Mehul Tulsidas Dattani

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Cell Types ◽

Hormone Deficiency ◽

Pituitary Hormone ◽

Gene Encoding ◽

Complex Disorders ◽

Signalling Molecules ◽

Pituitary Development ◽

Transgenic Murine Models

The anterior pituitary gland is a central regulator of growth, reproduction and homeostasis, and is the end-product of a carefully orchestrated pattern of expression of signalling molecules and transcription factors leading to the development of this complex organ secreting six hormones from five different cell types. Naturally occurring and transgenic murine models have demonstrated a role for many of these molecules in the aetiology of combined pituitary hormone deficiency (CPHD). These include the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, TBX19, SOX2 and SOX3. The expression pattern of these transcription factors dictates the phenotype that results when the gene encoding the relevant transcription factor is mutated. The highly variable phenotype may consist of isolated hypopituitarism, or more complex disorders such as septo-optic dysplasia and holoprosencephaly. Since mutations in any one transcription factor are uncommon, and since the overall incidence of mutations in known transcription factors is low in patients with CPHD, it is clear that many genes remain to be identified, and the characterization of these will further elucidate the pathogenesis of these complex conditions and also shed light on normal pituitary development.

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From Pituitary Stem Cell Differentiation to Regenerative Medicine

Frontiers in Endocrinology ◽

10.3389/fendo.2020.614999 ◽

2021 ◽

Vol 11 ◽

Author(s):

Maria Andrea Camilletti ◽

Julian Martinez Mayer ◽

Sebastian A. Vishnopolska ◽

Maria Ines Perez-Millan

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Embryonic Stem ◽

Stem Cell Differentiation ◽

Cell Types ◽

Anterior Lobe ◽

Pituitary Hormone ◽

Target Organs ◽

Polypeptide Hormones ◽

Induced Pluripotent

The anterior pituitary gland is comprised of specialized cell-types that produce and secrete polypeptide hormones in response to hypothalamic input and feedback from target organs. These specialized cells arise during embryonic development, from stem cells that express SOX2 and the pituitary transcription factor PROP1, which is necessary to establish the stem cell pool and promote an epithelial to mesenchymal-like transition, releasing progenitors from the niche. Human and mouse embryonic stem cells can differentiate into all major hormone-producing cell types of the anterior lobe in a highly plastic and dynamic manner. More recently human induced pluripotent stem cells (iPSCs) emerged as a viable alternative due to their plasticity and high proliferative capacity. This mini-review gives an overview of the major advances that have been achieved to develop protocols to generate pituitary hormone-producing cell types from stem cells and how these mechanisms are regulated. We also discuss their application in pituitary diseases, such as pituitary hormone deficiencies.

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