Failure to properly regenerate and maintain tissues is a root cause of disease and aging. One goal of regenerative biology is to unveil mechanisms by which simpler model organisms successfully regenerate so that we can b...Failure to properly regenerate and maintain tissues is a root cause of disease and aging. One goal of regenerative biology is to unveil mechanisms by which simpler model organisms successfully regenerate so that we can better understand how to control the cellular and molecular switches in human tissues. Planarians have become a favored model system for these studies because of their amazing capacity to fully and rapidly regenerate following amputation, but also for their response to other stressors such as starvation. Planarians undergo proportional degrowth when starved, a unique process that balances stem cell proliferation and apoptotic cell death, autophagy-mediated cell turnover, and energy sensing. We chose a pharmacological approach to study autophagy in planarians by using chloroquine, an autophagy inhibitor. We found that head regression and tissue lysis were induced by chloroquine in whole planarians and that starved planarians were more sensitive than their fed counterparts. While chloroquine treatment did not prevent tissue regeneration following injury, it caused regeneration delays and disruptions in photoreceptor replacement. Finally, we show that an anterior-posterior gradient of chloroquine sensitivity exists in the planarian with prepharyngeal tissues exhibiting significantly low sensitivity. Together, our results extend our understanding of autophagic flux in planarian tissue regeneration and maintenance and establish a model by which an autophagic gradient exists in this highly regenerative system.
Most major organs, like muscles, bones, vessels and kidneys, develop from the mesoderm, one of three germ cell layers in triploblastic organisms. Sialic acids significantly affect embryonic development by regulating cell...Most major organs, like muscles, bones, vessels and kidneys, develop from the mesoderm, one of three germ cell layers in triploblastic organisms. Sialic acids significantly affect embryonic development by regulating cell division, migration and death through signaling pathways and cell adhesion, which support morphogenesis. Loss of early biosynthetic enzymes reduces embryonic viability and leads to complex phenotypes, while the loss of terminal enzymes primarily results in tissue-specific defects in mesoderm-derived organs. Key sialylated glycoproteins involved in the developmental processes of mesoderm and mesoderm-derived organs have been identified across various species as major effectors. These enzymes and glycoproteins are of significant interest and are discussed in the present review.
Int J Dev Biol
· 2024 Dec · PMID 39723529
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The neural crest (NC) is an embryonic cell population with high migratory capacity. It contributes to forming several organs and tissues, such as the craniofacial skeleton and the peripheral nervous system of vertebrates...The neural crest (NC) is an embryonic cell population with high migratory capacity. It contributes to forming several organs and tissues, such as the craniofacial skeleton and the peripheral nervous system of vertebrates. Both pre-migratory and post-migratory NC cells are plastic, adopting multiple differentiation paths by responding to different inductive environmental signals. Cephalic neural crest cells (CNCCs) give rise to most of the cartilage and bone tissues in the head. On the other hand, the mesenchymal potential of trunk neural crest cells (TNCCs) is sparsely detected in some animal groups. The mesenchymal potential of TNCCs can be unveiled through specific environmental conditions of NC cultures. In this study, we present evidence that FGF8 treatment can foster increased chondrogenic differentiation of TNCCs, particularly during treatment at the migratory stage. Additionally, we conducted a transcriptomic analysis of TNCCs in the post-migratory stage, noting that exogenous FGF8 signaling can sustain multipotent status and, possibly, at the same time, a pro-cartilage regulatory gene network. Our results provide a more comprehensive understanding of the mechanisms underlying chondrogenic differentiation from TNCCs.
Krawczyk K, Oślislok M, Gałązkiewicz A
… +2 more, Szpila M, Maleszewski M
Int J Dev Biol
· 2024 Dec · PMID 39723528
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Aggregates of two mouse embryos produce viable offspring of normal size, indicating that there are mechanisms in the embryo that can downregulate their size to the size of the corresponding normal (single) embryos. Very...Aggregates of two mouse embryos produce viable offspring of normal size, indicating that there are mechanisms in the embryo that can downregulate their size to the size of the corresponding normal (single) embryos. Very little is known about the mechanisms controlling compensation for increased preimplantation size. Also, it is still elusive when exactly during development chimeric embryos regulate their size. Here, we determined the exact period of size regulation in chimeras. Using a chimeric embryo produced by aggregating two 8-cell stage embryos, we revealed that size regulation initiates shortly after implantation (E5.5) and ends with the start of gastrulation (E7.5). Importantly, processes that regulate cell number in chimeric embryos do not disturb morphogenesis, so that the formation of the proamniotic cavity occurs in parallel with size regulation.
Faisal M, Mehreen A, Hays D
… +2 more, Yaseen F, Liang Y
Int J Dev Biol
· 2024 Dec · PMID 39723527
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The axolotl, a legendary creature with the potential to regenerate complex body parts, is positioned as a powerful model organism due to its extraordinary regenerative capabilities. Axolotl can undergo successful regener...The axolotl, a legendary creature with the potential to regenerate complex body parts, is positioned as a powerful model organism due to its extraordinary regenerative capabilities. Axolotl can undergo successful regeneration of multiple structures, providing us with the opportunity to understand the factors that exhibit altered activity between regenerative and non-regenerative animals. This comprehensive review will explore the mysteries of axolotl regeneration, from the initial cellular triggers to the intricate signaling cascades that guide this complex process. We will delve deeply into the multifaceted interplay of genes and factors, highlighting the key role of signaling pathways and the influence of epigenetic modifications (such as DNA methylation, histone modification, and miRNA regulation) during regeneration. Furthermore, we will discuss how axolotls defy the odds by showing remarkable resistance to cancer, offering insights into potential therapeutic strategies. However, that is not the end; we will also highlight how age might affect the regenerative power of this creature. We hope this review will help navigate the awe-inspiring realm of axolotl regeneration, advance our understanding of regenerative biology, and chart pathways for future investigations aimed at uncovering new therapeutic approaches.
Wnt4 signaling is critical for mammalian female sex determination, in female reproductive organ development, in follicular and oocyte maturation, and in steroid hormone production. When Wnt4 function is impaired, female...Wnt4 signaling is critical for mammalian female sex determination, in female reproductive organ development, in follicular and oocyte maturation, and in steroid hormone production. When Wnt4 function is impaired, female embryos undergo partial female to male sex-reversal. This phenotype is associated with the expression of a set of somatic genes that are typical for the male differentiation pathways such as those of the Leydig cells. Given the roles of the 3`untranslated region () in control of gene expression, we addressed whether a knock-in of a stop cassette to 3`END of the gene would impact female reproductive system development or function. The cassette indeed affected gene expression so that the respective mRNA was upregulated in the ovaries of a three month-old female. The homozygous mice were noted to be leaner than their wild type (WT) littermate controls. Analysis of the ovarian follicular count at the age of three months revealed increased pre-antral but reduced ovarian corpus luteum follicular counts. Furthermore, two out of five of the homozygous female mice had ovarian cysts, not noted in WT controls. RT-qPCR and hybridization analysis depicted changes in the expression of a panel of genes which encode enzymes that mediate the synthesis of female steroid hormones or their receptors due to the knock-in. Thus, female mice which had the homozygous construct exhibited elevated ovarian mRNA expression and the corresponding knock-in was associated with changes in ovarian development and folliculogenesis. Our data reinforce the conclusion that deregulated expression impacts female sex organogenesis, ovary development and function, and that the knock-in mouse provides a model to explore in more detail the roles of Wnt4 signaling in the process.
Int J Dev Biol
· 2024 Aug · PMID 39177100
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The digestive tract is a series of organs with specific functions and specialized anatomy. Each organ is organized similarly with concentric layers of epithelial, connective, smooth muscle, and neural tissues. Interstiti...The digestive tract is a series of organs with specific functions and specialized anatomy. Each organ is organized similarly with concentric layers of epithelial, connective, smooth muscle, and neural tissues. Interstitial cells of Cajal (ICC) are distributed in smooth muscle layers and contribute to the organization of repetitive and rhythmic smooth muscle contractions. Understanding ICC development is critical to understanding gastrointestinal motility patterns. Experiments determining ICC origin and development in mice, chicken, and humans are described, as well as what is known in the zebrafish. At least six types of ICC in the digestive tract have been described and ICC heterogeneity in adult tissues is reviewed. Factors required for ICC development and for maintenance of ICC subclasses are described. This review is suitable for those new to ICC development and physiology, especially those focused on using zebrafish and other model systems.
Aldersey JE, Chen T, Petrovski K
… +2 more, Williams JL, Bottema CDK
Int J Dev Biol
· 2024 Aug · PMID 39177099
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The presence of horns in domestic ruminants, such as cattle, sheep and goats, has financial and welfare implications. The genetic interactions that lead to horn development are not known. Hornless, or polled, cattle occu...The presence of horns in domestic ruminants, such as cattle, sheep and goats, has financial and welfare implications. The genetic interactions that lead to horn development are not known. Hornless, or polled, cattle occur naturally. The known causative DNA variants (Celtic, Friesian, Mongolian and Guarani) are in intergenic regions on bovine chromosome 1, but their functions are not known. It is thought that horns may be derived from cranial neural crest stem cells and the POLLED variants disrupt the migration or proliferation of these cells. Relaxin family peptide receptor 2 () is more highly expressed in developing horns in cattle compared to nearby skin and has been shown to play a role in horn development in sheep. However, the role of RXFP2 in horn formation is not understood. Histological analyses of cranial tissues from homozygous horned and polled cattle fetuses at day 58 of development was carried out to determine the differences in the structure of the horn bud region. Condensed cells were only observed in the horn bud mesenchyme of horned fetuses and could be the progenitor horn cells. The distribution of neural crest markers (SOX10 and NGFR) and RXFP2 between horned and polled tissues by immunohistochemistry was also analysed. However, SOX10 and NGFR were not detected in the condensed cells, and therefore, these cells are either not derived from the neural crest, or have differentiated and no longer express neural crest markers. SOX10 and NGFR were detected in the peripheral nerves, while RXFP2 was detected in peripheral nerves and in the horn bud epidermis. Previous research has shown that RXFP2 variants are associated with horn phenotypes in cattle an sheep. Therefore, the RXFP2 variants may affect the development of the epidermis or peripheral nerves in the horn bud.
Lymphatic vessels within different organs have diverse developmental origins, depend on different growth factor signaling pathways for their development and maintenance, and display notable tissue-specific adaptations th...Lymphatic vessels within different organs have diverse developmental origins, depend on different growth factor signaling pathways for their development and maintenance, and display notable tissue-specific adaptations that contribute to their roles in normal physiology and in various diseases. Functional studies on the lymphatic vasculature rely extensively on the use of mouse models that allow selective gene targeting of lymphatic endothelial cells (LECs). Here, we discuss LEC diversity and provide an overview of some of the commonly used LEC-specific inducible Cre lines and induction protocols, outlining essential experimental parameters and their implications. We describe optimized treatment regimens for embryonic, postnatal and adult LECs, efficiently targeting organs that are commonly studied in lymphatic vascular research, such as the mesentery and skin. We further highlight the anticipated outcomes and limitations associated with each induction scheme and mouse line. The proposed protocols serve as recommendations for laboratories initiating studies involving targeting of the lymphatic vasculature, and aim to promote uniformity in lineage tracing and functional studies within the lymphatic vascular field.
Understanding the structure and function of cells is central to cell biology and physiology. The ability to control cell function may benefit biomedicine, such as cell-replacement therapy or regeneration. If structure de...Understanding the structure and function of cells is central to cell biology and physiology. The ability to control cell function may benefit biomedicine, such as cell-replacement therapy or regeneration. If structure defines function and cells are composed of water, lipids, small metabolites, nucleic acids, and proteins, of which the latter are largely encoded by the DNA present in the same cell, then one may assume that the cell types and variation in cellular phenotypes are shaped by differential gene expression. Cells of the same cell type maintain a similar composition. In this review, I will discuss the epigenetic and transcription regulation mechanisms guiding cell fate- specific gene expression in developing neural cells. Differentiation involves processes of cell-fate selection, commitment and maturation, which are not necessarily coupled.
Martini D, De Cesari C, Digregorio M
… +4 more, Muscò A, Giudetti G, Giannaccini M, Andreazzoli M
Int J Dev Biol
· 2024 Jul · PMID 39016375
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The tRNA-histidine guanylyltransferase 1-like (), also known as induced in high glucose-1 (), encodes for an essential mitochondria-associated protein highly conserved throughout evolution, that catalyses the 3'-5' addit...The tRNA-histidine guanylyltransferase 1-like (), also known as induced in high glucose-1 (), encodes for an essential mitochondria-associated protein highly conserved throughout evolution, that catalyses the 3'-5' addition of a guanine to the 5'-end of tRNA-histidine (tRNA). Previous data indicated that THG1L plays a crucial role in the regulation of mitochondrial biogenesis and dynamics, in ATP production, and is critically involved in the modulation of apoptosis, cell-cycle progression and survival, as well as in cellular stress responses and redox homeostasis. Dysregulations of THG1L expression play a central role in various pathologies, including nephropathies, and neurodevelopmental disorders often characterized by developmental delay and cerebellar ataxia. Despite the essential role of THG1L, little is known about its expression during vertebrate development. Herein, we examined the detailed spatio-temporal expression of this gene in the developing . Our results show that is maternally inherited and its temporal expression suggests a role during the earliest stages of embryogenesis. Spatially, mRNA localizes in the ectoderm and marginal zone mesoderm during early stages of development. Then, at tadpole stages, transcripts mostly localise in neural crests and their derivatives, somites, developing kidney and central nervous system, therefore largely coinciding with territories displaying intense energy metabolism during organogenesis in .
Esmaeli M, Barazesh M, Karimi Z
… +2 more, Roshankhah S, Ghanbari A
Int J Dev Biol
· 2024 Jul · PMID 39016374
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During embryonic development, the vertebrate embryonic epiblast is divided into two parts including neural and superficial ectoderm. The neural plate border (NPB) is a narrow transitional area which locates between these...During embryonic development, the vertebrate embryonic epiblast is divided into two parts including neural and superficial ectoderm. The neural plate border (NPB) is a narrow transitional area which locates between these parts and contains multipotent progenitor cells. Despite its small size, the cellular heterogeneity in this region produces specific differentiated cells. Signaling pathways, transcription factors, and the expression/repression of certain genes are directly involved in these differentiation processes. Different factors such as the Wnt signaling cascade, fibroblast growth factor (FGF), bone morphogenetic protein (BMP) signaling, and Notch, which are involved in various stages of the growth, proliferation, and differentiation of embryonic cells, are also involved in the determination and differentiation of neural plate border stem cells. Therefore, it is essential to consider the interactions and temporospatial coordination related to cells, tissues, and adjacent structures. This review examines our present knowledge of the formation of the neural plate border and emphasizes the requirement for interaction between different signaling pathways, including the BMP and Wnt cascades, the expression of its special target genes and their regulations, and the precise tissue crosstalk which defines the neural crest fate in the ectoderm at the early human embryonic stages.
Int J Dev Biol
· 2024 Jul · PMID 39016373
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Invertebrate and vertebrate species have many unusual cellular structures, such as long- or short-lived cell-in-cell structures and coenocytes. Coenocytes (often incorrectly described as syncytia) are multinuclear cells...Invertebrate and vertebrate species have many unusual cellular structures, such as long- or short-lived cell-in-cell structures and coenocytes. Coenocytes (often incorrectly described as syncytia) are multinuclear cells derived, unlike syncytia, not from the fusion of multiple cells but from multiple nuclear divisions without cytokinesis. An example of a somatic coenocyte is the coenocytic blastoderm in An astonishing property of coenocytes is the ability to differentiate the nuclei sharing a common cytoplasm into different subpopulations with different fate trajectories. An example of a germline coenocyte is the oogenic precursor of appendicularian tunicates, which shares many features with the somatic coenocyte of The germline coenocyte (coenocyst) is quite an unexpected structure because in most animals, including , and mice, oogenesis proceeds within a group (cyst, nest) of sibling cells (cystocytes) connected by the intercellular bridges (ring canals, RCs) derived from multiple divisions with incomplete cytokinesis of a progenitor cell called the cystoblast. Here, I discuss the differences and similarities between cystocyte-based and coenocyst-based oogenesis, and the resemblance of coenocystic oogenesis to coenocytic somatic blastoderm in I also describe cell-in-cell structures that although not mechanistically, cytologically, or molecularly connected to somatic or germline coenocytes, are both unorthodox and intriguing cytological phenomena rarely covered by scientific literature.
Int J Dev Biol
· 2024 Jun · PMID 38869222
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Mutations in the gene encoding Tre2/Bub2/Cdc16 (TBC)1 domain family member 24 (TBC1D24) protein are associated with a variety of neurological disorders, ranging from non-syndromic hearing loss to drug-resistant lethal ep...Mutations in the gene encoding Tre2/Bub2/Cdc16 (TBC)1 domain family member 24 (TBC1D24) protein are associated with a variety of neurological disorders, ranging from non-syndromic hearing loss to drug-resistant lethal epileptic encephalopathy and DOORS syndrome [Deafness, Onychodystrophy, Osteodystrophy, intellectual disability (formerly referred to as mental Retardation), and Seizures]. TBC1D24 is a vesicle-associated protein involved in neural crest cell and neuronal migration, maturation, and neurotransmission. In the cochlea, TBC1D24 has been detected in auditory neurons, but few reliable and convergent data exist about the sensory epithelium. Here, the expression of TBC1D24 has been characterized via immunolabelling throughout the postnatal maturation of the mouse cochlear sensory epithelium. TBC1D24 was detected in glia-like non-sensory epithelial cells during early developmental stages. In contrast, TBC1D24 was virtually absent in adjacent sensory hair cells. This expression distinguishing non-sensory from sensory epithelial cells almost disappears around the onset of hearing. Until now, TBC1D24 was mainly described as a neuronal protein either in the brain or in the cochlea. The present observations suggest that TBC1D24 could also regulate vesicle trafficking in cochlear glia-like non-sensory epithelial cells. For a long time, research about epilepsy has been mainly neurocentric. However, there is now evidence proving that glial cell dysregulation contribute to pathogenesis of epilepsy and neurodevelopmental disorders. As a consequence, exploring the possibility that TBC1D24 could also have a role in glial cells of the central nervous system could help to gain insight into TBC1D24-related neurological pathogenesis.
Enhancers play an essential role in gene regulation by receiving cues from transcription factors and relaying these signals to modulate transcription from target promoters. Enhancer-promoter communications occur across l...Enhancers play an essential role in gene regulation by receiving cues from transcription factors and relaying these signals to modulate transcription from target promoters. Enhancer-promoter communications occur across large linear distances of the genome and with high specificity. The molecular mechanisms that underlie enhancer-mediated control of transcription remain unresolved. In this review, we focus on research in uncovering the molecular mechanisms governing enhancer-promoter communication and discuss the current understanding of developmental gene regulation. The functions of protein acetylation, pausing of RNA polymerase II, transcriptional bursting, and the formation of nuclear hubs in the induction of tissue-specific programs of transcription during zygotic genome activation are considered.
Int J Dev Biol
· 2024 May · PMID 38770835
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Understanding the evolution of body plans has been one of the major areas of investigation in developmental and evolutionary biology. Cnidaria, the sister group to bilaterians, provides an opportunity to elucidate the or...Understanding the evolution of body plans has been one of the major areas of investigation in developmental and evolutionary biology. Cnidaria, the sister group to bilaterians, provides an opportunity to elucidate the origin and evolution of body axes. , a freshwater cnidarian, is a useful model to study signaling pathways governing pattern formation, which are conserved up to vertebrates including humans. The transforming growth factor β (TGF-β) signaling pathway is one of the fundamental pathways that regulate axis formation and organogenesis during embryonic development. In this article, we discuss the TGF-β pathway members identified in along with other cnidarians with an emphasis on bone morphogenetic proteins (BMPs) and their inhibitors. TGF-β members, especially those involved in BMP signaling pathway, are mainly involved in maintaining the Organizer region and patterning the body axis in . Identification of other members of this pathway in and fellow cnidarians would provide insights into the evolution of body axes and pattern formation in more complex metazoans.
The development of skin appendages, including hair follicles, teeth and mammary glands is initiated through the formation of the placode, a local thickening of the epithelium. The Wnt/β-catenin signaling cascade is an ev...The development of skin appendages, including hair follicles, teeth and mammary glands is initiated through the formation of the placode, a local thickening of the epithelium. The Wnt/β-catenin signaling cascade is an evolutionary conserved pathway with an essential role in placode morphogenesis, but its downstream targets and their exact functions remain ill defined. In this study, we identify () as a novel target of the Wnt/β-catenin pathway and demonstrate its expression pattern in the signaling centers of developing hair follicles and teeth. Ascl transcription factors belong to the superfamily of basic helix-loop-helix transcriptional regulators involved in cell fate determination in many tissues. However, their specific role in the developing skin remains largely unknown. We report that null mice have no overt phenotype. Absence of Ascl4 did not impair hair follicle morphogenesis or hair shaft formation suggesting that it is non-essential for hair follicle development. No tooth or mammary gland abnormalities were detected either. We suggest that other transcription factors may functionally compensate for the absence of Ascl4, but further research is warranted to assess this possibility.
During the initial days of development, the embryo gradually shifts from reliance on maternally provided RNAs and proteins to regulation of its own development. This transition is marked by embryonic genome activation (E...During the initial days of development, the embryo gradually shifts from reliance on maternally provided RNAs and proteins to regulation of its own development. This transition is marked by embryonic genome activation (EGA). While the factors driving human EGA remain poorly characterized, accumulating evidence suggests that double homeobox 4 (DUX4) is an important regulator of this process. Despite advances in single-cell methods which have allowed studies in early human embryos, fundamental questions regarding the function and regulation of DUX4 persist. Here, we review current knowledge of DUX4 with a focus on EGA in humans.
The megasporangium serves as a model system for understanding the concept of individual cell identity, and cell-to-cell communication in angiosperms. As development of the ovule progresses, three distinct layers, the epi...The megasporangium serves as a model system for understanding the concept of individual cell identity, and cell-to-cell communication in angiosperms. As development of the ovule progresses, three distinct layers, the epidermal (L1), the subepidermal or the hypodermal (L2) and the innermost layers (L3) are formed along the MMC (megaspore mother cell). The MMC, which is the primary female germline cell, is initiated as a single subepidermal cell amongst several somatic cells. MMC development is governed by various regulatory pathways involving intercellular signaling, small RNAs and DNA methylation. The programming and reprograming of a single nucellar cell to enter meiosis is governed by 'permissive' interacting processes and factors. Concomitantly, several nucellar sister cells are prevented from germline fate also by a set of 'repressive' factors. However, in certain angiosperms, anomalies in development of the female gametophyte have been observed. The sporophytic tissue surrounding the female gametophyte affects the gametophyte in multiple ways. The role of genes and transcription factors in the development of the MMC and in the regulation of various processes studied in selected model plants such as is explained in detail in this paper. However, as angiosperms display enormous diversity, it is important to investigate early stages of megasporogenesis in other plant systems as well. Such studies provide valuable insights in understanding the regulation of megasporogenesis and the evolution of the female gametophyte from gymnosperms to flowering plants.
(K17) is thought to be a candidate target gene for regulation by Lymphoid Enhancer Factor-1 (Lef-1) K17 is a marker that distinguishes junctional epithelium (JE) from epithelial rests of Malassez (ERM). However, the rela...(K17) is thought to be a candidate target gene for regulation by Lymphoid Enhancer Factor-1 (Lef-1) K17 is a marker that distinguishes junctional epithelium (JE) from epithelial rests of Malassez (ERM). However, the relationship of Lef-1 to K17 is not clear in this context. Moreover, the expression of other keratins such as K5, K6, K7 and K16 is not reported. Therefore, the aim of our study was to assay the expression of K5, K6, K7, K14, K16, K17 and Lef-1 in postnatal developing teeth, and clarify the corresponding immunophenotypes of the JE and ERM. Upper jaws of Wistar rats aged from postnatal (PN) day 3.5 to PN21 were used and processed for immunohistochemistry. K5 and K14 were intensely expressed in inner enamel epithelium (IEE), reduced enamel epithelium (REE), ERM and JE. There was no staining for K16 in the tissue, except for strong staining in the oral epithelium. Specifically, at PN3.5 and PN7, K17 was initially strongly expressed and then negative in the IEE. At PN16 and PN21, both REE and ERM were strongly stained for K17, whereas K17 was negative in the JE. In addition, K6, K7 and Lef-1 were not detected in any tissue investigated. REE and ERM have an identical keratin expression pattern before eruption, while JE differs from ERM in the expression of K17 after eruption. The expression of K17 does not coincide with that of Lef-1. These data indicate that JE has a unique phenotype different from ERM, which is of odontogenic origin.