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As a result, the PGC progenitors must repress the cell-autonomous effects of maternally encoded transcription factors, in addition to repressing the response to external stimuli. For example, in Xenopus embryos, germ plasm counters the potential effects of VegT, which is an endodermal determinant whose RNA is also localized to the vegetal hemisphere and inherited by the PGCs Venkatarama et al. Germ plasm is also essential for the development of PGCs in zebrafish Hashimoto et al.
RNA encoding Vasa was the first germ plasm marker cloned from zebrafish Olsen et al. In almost all of these respects, zebrafish oocytes resemble those of Xenopus though Xenopus vasa RNA is not localized; Komiya et al.
Recording and contextualizing the science of embryos, development, and reproduction.
Bucky ball expression is necessary and sufficient for the organization of zebrafish germ plasm Bontems et al. Homologs of Bucky ball have been identified in other vertebrates, but it is unknown whether these also participate in germ plasm organization. Post-fertilization, germ plasm RNAs segregate to the distal ends of the cleavage furrows, away from the bottom of the yolky mass. The method of translocation of zebrafish germ plasm RNAs from the bottom of the yolk mass to the top tier of the embryo is not fully understood, and indeed individual RNA species are recruited to the animal hemisphere by different pathways Theusch et al.
It is important to note, in addition, that in frog embryos, germ plasm is not translocated to the animal hemisphere, so the embryological location in which germ plasm functions in Xenopus and zebrafish embryos is not conserved see Fig. Figure 1 Download Figure Download figure as PowerPoint slide Germ plasm localizes to different regions of zebrafish and Xenopus embryos. Germ plasm represented in red is localized to the vegetal hemisphere in oocytes of zebrafish and Xenopus. In zebrafish, the germ plasm translocates from the vegetal hemisphere of oocytes to the cleavage furrows in the animal hemisphere of early embryos see Raz In Xenopus embryos, germ plasm incorporates into vegetal blastomeres of early embryos, and PGCs are sister cells to the somatic endoderm.
Understanding how germ plasm evolved in teleost fish is more confusing than in frogs because the mechanisms are not conserved across all species. To clarify when the localization of germ plasm RNAs evolved in teleosts, we turned to sturgeons, which retain the embryological characteristics of ancient Actinopterygii. We cloned the vasa and dazl orthologs from gulf sturgeons Acipenser oxyrhynchus and hybridized probes from these molecules to sections from adult ovaries containing growing as well as fully-grown oocytes.
Sturgeon dazl RNA Fig. In no case did we identify localized expression of either vasa or dazl RNAs in sturgeon oocytes, regardless of oocyte size. From these data, we conclude that germ plasm evolved sometime after the divergence of teleosts from more primitive lineages. Ovary from the gulf sturgeon Acipenser oxyrhynchus was sectioned and hybridized with sense probe corresponding to the sturgeon dazl gene A or antisense probes against vasa B and C and dazl D and E.
Arrows show oocytes. Staining pattern indicates the absence of RNA localization. Nieuwkoop reported that cells in the primitive ectoderm animal cap of axolotl embryos could be induced to form PGCs, and is thus credited with identifying regulative germ cell specification in vertebrates.
But as a concept, this hypothesis did not receive serious attention until equivalent findings were reported in mouse embryos. This was accomplished in two landmark studies. These studies established the principle that mouse PGCs are not predetermined, but are specified relatively late in development. To resolve the problem that two distinct modes of germ cell specification exist in vertebrates, Johnson et al.
Strong support for this hypothesis comes from studies with turtles, representing reptiles. Turtle oocytes lack germ plasm, and PGCs are generated in the primitive streak, suggesting they are specified by induction Bachvarova et al. From comparisons between turtles and mammals with axolotls, it is possible to conclude that epigenesis was conserved from urodele-like amphibians to the basal amniotes from which mammals evolved. Epigenesis in mammals has been most intensely studied in mice.
In vitro , epiblasts dissected between E5. An early response to BMP4 about E6. As a result, specification towards mesoderm is reversed, and PGCs are redirected towards germ line development. Superficially, these effects of BLIMP1 are reminiscent of those of germ plasm in frogs and invertebrates, i. However, BLIMP1 does not induce global transcriptional repression; rather, it accomplishes germ lineage restriction by inhibiting expression of specific genes in an actively transcribing cell Surani et al. Furthermore, it is concomitant with arrest in G2 of the cell cycle and the epigenetic remodeling characteristics of migratory PGCs Seki et al.
Therefore, polII inhibition in the mouse germ line is unlikely to be a component of the specification process. Nevertheless, it is tempting to speculate that polII inhibition is conserved. One possibility is that polII suppression was advanced to an earlier, specification, stage of development by the evolution of germ plasm. But clarification of this issue will require investigation in more primitive species that employ epigenesis.
As yet, it is unclear whether PGC specification in mouse embryos is representative of mammals at large. However, this will only become clear from work with other experimental systems. Nonetheless, it is evident that epigenesis, as a process, is conserved in mammals. Among lower vertebrates, regulative specification has only been investigated in detail in embryos from axolotls.
Axolotls are particularly useful because they resemble the tetrapod ancestors Ahlberg et al. They pass over the blastopore during gastrulation, and by tailbud stage, bonafide PGCs can be detected in the posterior compartment of the dorsal—lateral mesoderm Johnson et al. However, they do not initiate expression of germ cell-specific genes dazl and vasa homologs until early tailbud stages.
In accordance with this, robust induction of PGCs from animal caps is achieved with a combination of fibroblast growth factor FGF and BMP signals, and these signals are also required in intact embryos, suggesting they are the natural inducers of the axolotl germ line M O'Reilly, R F Bachvarona and A D Johnson, unpublished observations. Therefore, the block to somatic specification is finite in axolotls, and is not like the complete repression of somatic cell fate that is affected in Xenopus embryos by germ plasm. Importantly, these studies highlight a major difference in the developmental potential of axolotl and Xenopus animal caps, since Xenopus animal caps cannot be made to produce PGCs Michael Intruigingly, the first decision made by cells in an axolotl animal cap is a commitment to either the germ line or soma, in a process regulated by Nanog activity Z Ferjentsik and A D Johnson, unpublished observations.
This initial regulatory step in development is not conserved in the cells from Xenopus animal caps, whose potential is restricted to the production of somatic cell types, and therefore, cells in the animal cap of frog embryos initiate development downstream of the pluripotent ground state. It is fascinating to speculate on how this somatically primed pluripotent state evolved, but it can be assumed that its evolution contributes to the more rapid development of frog embryos, and was therefore a selective advantage.
The unrestricted potential of cells in the pluripotent ground state pluripotent cells is an essential component of epigenesis, so it would be assumed to be conserved in chordates. In fact, molecules with NANOG activity have been identified as far back as hemichordates J Dixon and A D Johnson, unpublished observations , at the base of deuterostomes, suggesting that pluripotency is ancestral to chordates. However, pluripotency is not uniformly conserved. For instance, in Xenopus and zebrafish, the pluripotency network is not conserved.
Nanog was deleted from the frog genome some time after the anuran and urodele lineages diverged from their last common amphibian ancestor Dixon et al. In the phylum Chordata, the notochordal area is the central region around which the other areas are oriented Chap.
The major presumptive organ-forming areas of the late blastula exist in various degrees of differentiation Chap. This is the process which effects a reorientation of the presumptive organ-forming areas and brings about their axiation antero-posteriorly in relation to the notochordal axis and the future embryonic body Chap. During gastrulation the major organ-forming areas are subdivided into minor areas or fields, each field being restricted to the development of a particular organ or part.
As the development of various vertebrate embryos is strikingly similar up to this point, the primitive embryonic body forms of all vertebrates resemble each other Chap.
The role of the organizer and neural induction
In the drawings presented in Part III, the following scheme for designating the major organ-forming areas existing within the three germ layers is adhered to:. Cleavage Segmentation and Blastulation. The Chordate Blastula and Its Significance. Description of the various types of chordate blastulae with an outline of their organforming areas. Summary of morphogenetic movements of cells during gastrulation in the frog and other Amphibia.
Tabulation of the neural, epidermal, entodermal, and mesodermal, organ-forming areas in the vertebrate group. Tabulation coelom formation and other features involved in the early differentiation of the mesodermal areas. Tubulation of the neural, epidermal, entodermal, and mesodermal, organ-forming areas in Amphioxus. Comparison of the problems of tubulation in the embryo of Amphioxus with that of the embryos in the subphylum Vertebrata.
Segregation of the entoderm from the chordamesoderm and the formation of the primitive metenteric tube.
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The limb bud as an illustration of the field concept of development in relation to the gastrula and the tubulated embryo. Navigation Main page. Site map. Site updates. Recent changes. New images. Teaching Medicine. BGD2 Tutorial. Med Projects. Yano et al. These neurons to a large extent developed early, around E13—E In male and female rats, both Quenell et al.
Iwasa et al. In accordance with these results, Poling et al. During development in male rats, sustained knockdown of GnIH led to increased plasma levels of LH and increased testicular growth These data indicate that GnIH act as inhibitor of gonadal maturation and puberty, similar to the situation in birds. However, Iwasa et al. This suggests that GnIH alone is not sufficient as inhibitor, but that regulation of sexual development is more complex, probably including additional factors such as other RFa, in addition to energy-related factors like ghrelin or leptin, or other.
In summary, the expression of a seemingly functional GnIH system in fish, birds, and mammals already from early development suggests important developmental function s of this RFa in vertebrates. See Table 3 for an overview over developmental studies of GnIH. Table 3. Overview of studies of GnIH in vertebrate development. Kisspeptins are RFa encoded by the Kiss gene. The resulting protein is further processed into bioactive peptides of variable lengths 94 , while their receptors belong to the rhodopsin family of G-protein-coupled receptors 95 — The product of the Kiss gene was first discovered as a metastasis suppressor and therefore termed metastin However, kisspeptins and their putative receptors Kissr or Gpr54 have during the last decade emerged as major gatekeepers of reproduction because of their central role in regulating the brain—pituitary—gonadal BPG axis [reviewed by Ref.
The importance of the Kiss system as a regulator of the BPG-axis came after observations that mutations in the Gpr lead to idiopathic hypogonadotropic hypogonadism , Besides its role as a tumor suppressor and regulator of the BPG-axis, several studies report additional roles of the Kiss system, including vasoconstriction , , neuronal migration, and increased synaptic transmission , For example, Fiorini et al.
Although detailed mechanisms of action are still lacking, these seemingly pleiotropic roles may reflect the diversity of intracellular signaling pathways that can be triggered by Kiss receptor activation , The current understanding in mammalian systems suggests that major endogenous and environmental signals act through Kiss neurons, which then directly or indirectly provide an integrated signal to the hypophysiotropic GnRH neurons.
This could at least partly be due to the lack of a suitable model system. Because Kiss or Gpr54 KO mice are infertile, homozygous offspring need to be established from heterozygous parents. This means that the possibility of maternal transfer of transcripts, including those of Kiss and Gpr54 , cannot be excluded in this system.
Furthermore, and common to all RFa families discussed here, studying embryonic development in mammals in vivo is difficult due to their viviparity. The few existing data on kisspeptins during early development come from studies in medaka and zebrafish. We recently performed a study of kisspeptin ligand and receptor expression pattern and function during early development in medaka, exploiting the advantages of the teleost model system In zebrafish, kiss1 and kiss2 gene expression was reported in 24 hpf 30 somite stage embryos , but earlier stages were not investigated.
In another teleost, the cobia Rachycentron canadum gpr expression was detected at 1 day post hatching The early expression of kiss and gpr54 also coincides with the early expression of gonadotropins in fish , indicating a potentially functional BPG-axis already during early embryogenesis. Figure 1. Kiss and kiss receptors are expressed at very early stages in medaka embryos. Key developmental stages are given above the age of the hours h or days d post-fertilization hpf.
Figure from Ref. In Hodne et al. Both maternally and zygotically expressed kiss1 and gpr seemed critical for proper development Figure 2. However, the apparent functions of the maternally and zygotically expressed transcripts were quite distinct, as explained below. Figure 2. Low dose antisense knockdown KD lead to impaired brain and eye development.
At 3 dpf, there was no development of the forebrain after kiss1 knockdown bottom right. Arrowheads point to the area of the developing eyes. Knockdown of maternal kiss1 and gpr led to developmental arrest and subsequent death around the blastula stage stage 10—11 , suggesting that this early expressed system could be involved either in regulation of early asynchronous cell division or early cell migration.
Moreover, sdf1 signaling is crucial for survival in mice, and individuals lacking either receptor or ligand have defective hematopoiesis, developmental lymphoid tissue, vascularization of gastrointestinal tract, migration of neuronal cells, and patterning in the central nervous system, and they die prenatally , Zygotic knockdown of kiss1 and gpr , on the other hand, allowed the embryos to survive gastrulation and a seemingly normal development continued until completion of neurulation stage At this point, early eye development is normally observed.
However, after zygotic knockdown with either morpholino or low dose of peptide nucleic acid PNA , eye development was interrupted, and further brain development was severely disrupted Figure 2. Surprisingly, knockdown of kiss2 , which was expressed at similar levels as kiss1 , did not produce any increased mortality or malformed embryos. Unless kiss1 takes over the role of kiss2 following kiss2 knockdown, kiss2 does not seem to be critical for proper development. The different effects observed following kiss1 and kiss2 knockdown suggest the possibility of a very early separation of two functional systems during embryonic development.
One system, comprised of Kiss1 and Gpr, has a functional role important for survival during the maternal stage of development. This system continues to function throughout embryonic development, although it seems more important for regulating brain development at later embryonic stages. A second system seems to be comprised of Kiss2 binding to either Gpr or other unknown RFa receptors. The possible function of this second system remains to be clarified.
Contrary to the observed phenotypes following zygotic knockdown of kiss1 and gpr outlined above, a moderate knockdown of medaka gpr arrested further development at stage 16 late gastrula. This phenotype resembled that of maternal kiss1 and gpr knockdowns. However, as gpr is first detected after transition to zygotic gene expression, new questions arise as to why a similar phenotype was not also observed after zygotic kiss1 and gpr knockdown.
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One explanation could be that the two receptors are functionally separated. If they are involved in similar functions, our results indicate that the actions of Gpr may be partly compensated for by Gpr, whereas Gpr cannot be functionally replaced by Gpr A recent work by Zhao et al. In line with Kitahashi et al. Furthermore, it was shown that both kiss ligands stimulated GnRH3 neuron proliferation peripherally, while only kiss1 stimulated proliferation and synaptic contact points of GnRH3 neurons in the TN and hypothalamic regions. The existence of a functional kisspeptin system in birds is not clarified [see in Ref.
In mammals, the kisspeptin system has been intensively investigated during the last decade. Whereas, most literature covers the key role of Kiss in regulating GnRH neuron around and after puberty, pre- and early neonatal stages have been looked into more closely during recent years [see reviews in Ref. For instance, Kiss1 gene expression has been detected in hypothalamic areas during the late fetal period in mice [stage E Gpr gene expression has also been detected in stage E Maternally provided Kiss ligands or receptors have, however, not been reported. It seems that the early kisspeptin systems are functional in rodents in that Kiss neurons already are in close contact with GnRH-neurons prenatally, and that GnRH-neurons are able to respond to kisspeptins by enhanced GnRH secretion during prenatal life , , , Based on these and several other studies, a more generalized picture is starting to appear with a seemingly functional kisspeptin system in place during the last part of gestation.
The Kiss neurons increase in number and activity and reach a peak prenatally, before a decreased activity around birth, and then a new increase again during early neonatal life before the activity decreases to low levels until the pre-pubertal stage. The prenatal and early neonatal peaks in Kiss neuron activity seemingly coincide with similar peaks in GnRH and pituitary gonadotropin secretion [see in Ref.
However, the function of this early expression of Kiss remains elusive. In line with the more severe phenotypes observed in medaka following receptor knockdown , Lapatto et al. As mice possess only the one Gpr54 paralog, one of several suggestions was a possible weak activation of Gpr by other ligands. The results of Hodne et al. Interestingly, Mayer and Boehm found that female mice with genetically ablated kisspeptin neurons underwent puberty and became fertile. In contrast, acute ablation in adult mice inhibited fertility. These results clearly indicate compensatory mechanisms for early loss of kisspeptins.
Whether maternally transferred kiss is crucial for mouse development has not been investigated. Although more data are available regarding the role of kisspeptins during vertebrate development compared to the role of other RFa, there are still much work to be done. See Table 4 for an overview over developmental studies of kisspeptins. Table 4. Overview of studies of kiss in vertebrate development. Both the receptor and ligand were present from early stages of adrenal development, mostly expressed in the adrenal cortex, but also in the medulla in human fetus.
Homozygous mice was viable, but they suffered from osteopenia reduced bone density , and the investigations suggested that the bone formation was arrested at an early stage. The knockout mice seemed to behave normally and were fertile. The RFa form a complex family with many different members acting in various physiological processes, with one peptide seemingly having several functions in the same animal in some cases. Common to all the peptides seems to be that they could have a role in appetite regulation, pain modulation, and reproduction.
With the newest member of the RFa family found only a little over 10 years ago, the field of RFa is relatively new and requires much more research. Especially, how these peptides can influence development is poorly understood. However, the few studies of RFa in developing vertebrates show interesting results that may indicate that many of the RFa could have a separate role in development. Interestingly, it seems that all RFa are expressed early in development in many different groups of vertebrates.
However, most of our knowledge of RFa comes from in situ hybridization and immunohistochemistry experiments. Very few functional studies have been conducted, so it is difficult to assess the role of this early expression. One knockdown study on medaka performed in our laboratory shows that kiss1 , gpr , and gpr play vital roles in early development in this fish species, and that these genes are probably important for proper brain development.
It will be very interesting to see if loss or gain of function could reveal novel functions of the other RFa. The cellular pathways of RFa are poorly understood, and more research is required to find out how RFa can act on developmental processes. RFa may also be important for the proper migration of neurons in the developing brain.
However, more research is needed to clarify the role of RFa in neuronal migration. Another interesting aspect of RFa is the fact that many of them can affect apoptosis and cell-cycle progression, possibly through affecting opioid receptors PrRP is also found to influence human lymphocyte proliferation In invertebrates, FMRFa has been found to inhibit apoptosis in a snail, indicating that the link between RFa and apoptosis is an evolutionary conserved mechanism Interestingly, NPFF gene expression in mammals is regulated by transcription factors also involved in cell-cycle regulation and apoptosis The field of RFa in vertebrates is exiting and rapidly expanding.
The few developmental studies that have been done show promising and important results.
Taken together, these studies indicate that RFa may have a role in development of the nervous system not yet identified. More research is needed, especially functional studies that can give insight into the role these peptides play in development. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Structure of a molluscan cardioexcitatory neuropeptide.
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Dev Brain Res 95 — Ontogeny of the F8Famide-like morphine-modulating peptides in the central nervous system of rats. Dev Dyn —9. Comparative immunocytochemical study of FMRFamide neuronal system in the brain of Danio rerio and Acipenser ruthenus during development. Dev Brain Res — Distribution and development of FMRFamide-like immunoreactive neuronal systems in the brain of the brown trout, Salmo trutta fario. Ontogenetic organization of the FMRFamide immunoreactivity in the nervus terminalis of the lungfish, Neoceratodus forsteri.
Distribution of FMRFamide-like immunoreactivity in the brain and pituitary of Rana esculenta during development. Brain Res Dev Brain Res 95 — J Chem Neuroanat 21 — Localization of FMRFamide-like immunoreactivity in the brain of the viviparous skink Chalcides chalcides. Brain Behav Evol 57 — Wirsig-Wiechmann CR. Brain Res —9. Characterization and distribution of FMRFamide immunoreactivity in the rat central nervous system. Peptides 5 —8. Extrabulbar olfactory system and nervus terminalis FMRFamide immunoreactive components in Xenopus laevis ontogenesis.
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