Category Archives: Stell Cell Genetics

In 1968, doctors performed the first successful bone marrow transplant. Bone marrow contains somatic stem cells that can produce all of the different cell types that make up our blood. It is transplanted routinely to treat a variety of blood and bone marrow diseases, blood cancers, and immune disorders. More recently, stem cells from the blood stream (called peripheral blood stem cells) and umbilical cord stem cells have been used to treat some of the same blood-based diseases.

Leukemia is a cancer of white blood cells, or leukocytes. Like other blood cells, leukocytes develop from somatic stem cells. Mature leukocytes are released into the bloodstream, where they work to fight off infections in our bodies.

Leukemia results when leukocytes begin to grow and function abnormally, becoming cancerous. These abnormal cells cannot fight off infection, and they interfere with the functions of other organs.

Successful treatment for leukemia depends on getting rid of all the abnormal leukocytes in the patient, allowing healthy ones to grow in their place. One way to do this is through chemotherapy, which uses potent drugs to target and kill the abnormal cells. When chemotherapy alone can't eliminate them all, physicians sometimes turn to bone marrow transplants.

In a bone marrow transplant, the patient's bone marrow stem cells are replaced with those from a healthy, matching donor. To do this, all of the patient's existing bone marrow and abnormal leukocytes are first killed using a combination of chemotherapy and radiation. Next, a sample of donor bone marrow containing healthy stem cells is introduced into the patient's bloodstream.

If the transplant is successful, the stem cells will migrate into the patient's bone marrow and begin producing new, healthy leukocytes to replace the abnormal cells.

New evidence suggests that bone marrow stem cells may be able to differentiate into cell types that make up tissues outside of the blood, such as liver and muscle. Scientists are exploring new uses for these stem cells that go beyond diseases of the blood.

While most blood stem cells reside in the bone marrow, a small number are present in the bloodstream. These peripheral blood stem cells, or PBSCs, can be used just like bone marrow stem cells to treat leukemia, other cancers and various blood disorders.

Since they can be obtained from drawn blood, PBSCs are easier to collect than bone marrow stem cells, which must be extracted from within bones. This makes PBSCs a less invasive treatment option than bone marrow stem cells. PBSCs are sparse in the bloodstream, however, so collecting enough to perform a transplant can pose a challenge.

Newborn infants no longer need their umbilical cords, so they have traditionally been discarded as a by-product of the birth process. In recent years, however, the stem-cellrich blood found in the umbilical cord has proven useful in treating the same types of health problems as those treated using bone marrow stem cells and PBSCs.

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Stem Cells In Use - Learn Genetics

During the latter stage stages of the 20th century, man harnessed the power of the atom, and not long after, soon realised the power of genes. Genetic engineering is going to become a very mainstream part of our lives sooner or later, because there are so many possibilities advantages (and disadvantages) involved. Here are just some of the advantages :

Of course there are two sides to the coin, here are some possible eventualities and disadvantages.

Genetic engineering may be one of the greatest breakthroughs in recent history alongside the discovery of the atom and space flight, however, with the above eventualities and facts above in hand, governments have produced legislation to control what sort of experiments are done involving genetic engineering. In the UK there are strict laws prohibiting any experiments involving the cloning of humans. However, over the years here are some of the experimental breakthroughs made possible by genetic engineering.

Genetic engineering has been impossible until recent times due to the complex and microscopic nature of DNA and its component nucleotides. Through progressive studies, more and more in this area is being made possible, with the above examples only showing some of the potential that genetic engineering shows.

For us to understand chromosomes and DNA more clearly, they can be mapped for future reference. More simplistic organisms such as fruit fly (Drosophila) have been chromosome mapped due to their simplistic nature meaning they will require less genes to operate. At present, a task named the Human Genome Project is mapping the human genome, and should be completed in the next ten years.

The process of genetic engineering involves splicing an area of a chromosome, a gene, that controls a certain characteristic of the body. The enzyme endonuclease is used to split a DNA sequence and split the gene from the rest of the chromosome. For example, this gene may be programmed to produce an antiviral protein. This gene is removed and can be placed into another organism. For example, it can be placed into a bacteria, where it is sealed into the DNA chain using ligase. When the chromosome is once again sealed, the bacteria is now effectively re-programmed to replicate this new antiviral protein. The bacteria can continue to live a healthy life, though genetic engineering and human intervention has actively manipulated what the bacteria actually is. No doubt there are advantages and disadvantages, and this whole subject area will become more prominent over time.

The next page returns the more natural circumstances of genetic diversity.

See the original post: Genetic Engineering Advantages & Disadvantages Biology

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Genetic Engineering Advantages & Disadvantages Biology ...

The potential therapeutic benefits of HESC research provide strong grounds in favor of the research. If looked at from a strictly consequentialist perspective, its almost certainly the case that the potential health benefits from the research outweigh the loss of embryos involved and whatever suffering results from that loss for persons who want to protect embryos. However, most of those who oppose the research argue that the constraints against killing innocent persons to promote social utility apply to human embryos. Thus, as long as we accept non-consequentialist constraints on killing persons, those supporting HESC research must respond to the claim that those constraints apply to human embryos.

In its most basic form, the central argument supporting the claim that it is unethical to destroy human embryos goes as follows: It is morally impermissible to intentionally kill innocent human beings; the human embryo is an innocent human being; therefore it is morally impermissible to intentionally kill the human embryo. It is worth noting that this argument, if sound, would not suffice to show that all or even most HESC research is impermissible, since most investigators engaged in HESC research do not participate in the derivation of HESCs but instead use cell lines that researchers who performed the derivation have made available. To show that researchers who use but do not derive HESCs participate in an immoral activity, one would further need to establish their complicity in the destruction of embryos. We will consider this issue in section 2. But for the moment, let us address the argument that it is unethical to destroy human embryos.

A premise of the argument against killing embryos is that human embryos are human beings. The issue of when a human being begins to exist is, however, a contested one. The standard view of those who oppose HESC research is that a human being begins to exist with the emergence of the one-cell zygote at fertilization. At this stage, human embryos are said to be whole living member[s] of the species homo sapiens [which] possess the epigenetic primordia for self-directed growth into adulthood, with their determinateness and identity fully intact (George & Gomez-Lobo 2002, 258). This view is sometimes challenged on the grounds that monozygotic twinning is possible until around days 1415 of an embryos development (Smith & Brogaard 2003). An individual who is an identical twin cannot be numerically identical to the one-cell zygote, since both twins bear the same relationship to the zygote, and numerical identity must satisfy transitivity. That is, if the zygote, A, divides into two genetically identical cell groups that give rise to identical twins B and C, B and C cannot be the same individual as A because they are not numerically identical with each other. This shows that not all persons can correctly assert that they began their life as a zygote. However, it does not follow that the zygote is not a human being, or that it has not individuated. This would follow only if one held that a condition of an entitys status as an individual human being is that it be impossible for it to cease to exist by dividing into two or more entities. But this seems implausible. Consider cases in which we imagine adult humans undergoing fission (for example, along the lines of Parfits thought experiments, where each half of the brain is implanted into a different body) (Parfit 1984). The prospect of our going out of existence through fission does not pose a threat to our current status as distinct human persons. Likewise, one might argue, the fact that a zygote may divide does not create problems for the view that the zygote is a distinct human being.

There are, however, other grounds on which some have sought to reject that the early human embryo is a human being. According to one view, the cells that comprise the early embryo are a bundle of homogeneous cells that exist in the same membrane but do not form a human organism because the cells do not function in a coordinated way to regulate and preserve a single life (Smith & Brogaard 2003, McMahan 2002). While each of the cells is alive, they only become parts of a human organism when there is substantial cell differentiation and coordination, which occurs around day-16 after fertilization. Thus, on this account, disaggregating the cells of the 5-day embryo to derive HESCs does not entail the destruction of a human being.

This account is subject to dispute on empirical grounds. That there is some intercellular coordination in the zygote is revealed by the fact that the development of the early embryo requires that some cells become part of the trophoblast while others become part of the inner cell mass. Without some coordination between the cells, there would be nothing to prevent all cells from differentiating in the same direction (Damschen, Gomez-Lobo and Schonecker 2006). The question remains, though, whether this degree of cellular interaction is sufficient to render the early human embryo a human being. Just how much intercellular coordination must exist for a group of cells to constitute a human organism cannot be resolved by scientific facts about the embryo, but is instead an open metaphysical question (McMahan 2007a).

Suppose that the 5-day human embryo is a human being. On the standard argument against HESC research, membership in the species Homo sapiens confers on the embryo a right not to be killed. This view is grounded in the assumption that human beings have the same moral status (at least with respect to possessing this right) at all stages of their lives.

Some accept that the human embryo is a human being but argue that the human embryo does not have the moral status requisite for a right to life. There is reason to think that species membership is not the property that determines a beings moral status. We have all been presented with the relevant thought experiments, courtesy of Disney, Orwell, Kafka, and countless science fiction works. The results seem clear: we regard mice, pigs, insects, aliens, and so on, as having the moral status of persons in those possible worlds in which they exhibit the psychological and cognitive traits that we normally associate with mature human beings. This suggests that it is some higher-order mental capacity (or capacities) that grounds the right to life. While there is no consensus about the capacities that are necessary for the right to life, some of the capacities that have been proposed include reasoning, self-awareness, and agency (Kuhse & Singer 1992, Tooley 1983, Warren 1973).

The main difficulty for those who appeal to such mental capacities as the touchstone for the right to life is that early human infants lack these capacities, and do so to a greater degree than many of the nonhuman animals that most deem it acceptable to kill (Marquis 2002). This presents a challenge for those who hold that the non-consequentialist constraints on killing human children and adults apply to early human infants. Some reject that these constraints apply to infants, and allow that there may be circumstances where it is permissible to sacrifice infants for the greater good (McMahan 2007b). Others argue that, while infants do not have the intrinsic properties that ground a right to life, we should nonetheless treat them as if they have a right to life in order to promote love and concern towards them, as these attitudes have good consequences for the persons they will become (Benn 1973, Strong 1997).

Some claim that we can reconcile the ascription of a right to life to all humans with the view that higher order mental capacities ground the right to life by distinguishing between two senses of mental capacities: immediately exercisable capacities and basic natural capacities. (George and Gomez-Lobo 2002, 260). According to this view, an individuals immediately exercisable capacity for higher mental functions is the actualization of natural capacities for higher mental functions that exist at the embryonic stage of life. Human embryos have a rational nature, but that nature is not fully realized until individuals are able to exercise their capacity to reason. The difference between these types of capacity is said to be a difference between degrees of development along a continuum. There is merely a quantitative difference between the mental capacities of embryos, fetuses, infants, children, and adults (as well as among infants, children, and adults). And this difference, so the argument runs, cannot justify treating some of these individuals with moral respect while denying it to others.

Given that a human embryo cannot reason at all, the claim that it has a rational nature has struck some as tantamount to asserting that it has the potential to become an individual that can engage in reasoning (Sagan & Singer 2007). But an entitys having this potential does not logically entail that it has the same status as beings that have realized some or all of their potential (Feinberg 1986). Moreover, with the advent of cloning technologies, the range of entities that we can now identify as potential persons arguably creates problems for those who place great moral weight on the embryos potential. A single somatic cell or HESC can in principle (though not yet in practice) develop into a mature human being under the right conditionsthat is, where the cells nucleus is transferred into an enucleated egg, the new egg is electrically stimulated to create an embryo, and the embryo is transferred to a womans uterus and brought to term. If the basis for protecting embryos is that they have the potential to become reasoning beings, then, some argue, we have reason to ascribe a high moral status to the trillions of cells that share this potential and to assist as many of these cells as we reasonably can to realize their potential (Sagan & Singer 2007, Savulescu 1999). Because this is a stance that we can expect nearly everyone to reject, its not clear that opponents of HESC research can effectively ground their position in the human embryos potential.

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Stell Cell Research Stem Cell Clinic

Embryonic stem cells (ES cells) are pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage preimplantation embryo.[1][2] Human embryos reach the blastocyst stage 45 days post fertilization, at which time they consist of 50150 cells. Isolating the embryoblast or inner cell mass (ICM) results in destruction of the blastocyst, which raises ethical issues, including whether or not embryos at the pre-implantation stage should be considered to have the same moral status as more developed human beings.[3][4]

Human ES cells measure approximately 14 m while mouse ES cells are closer to 8 m.[5]

Embryonic stem cells, derived from the blastocyst stage early mammalian embryos, are distinguished by their ability to differentiate into any cell type and by their ability to propagate. Embryonic stem cell's properties include having a normal karyotype, maintaining high telomerase activity, and exhibiting remarkable long-term proliferative potential.

Embryonic stem cells of the inner cell mass are pluripotent, that is, they are able to differentiate to generate primitive ectoderm, which ultimately differentiates during gastrulation into all derivatives of the three primary germ layers: ectoderm, endoderm, and mesoderm. These include each of the more than 220 cell types in the adult body. Pluripotency distinguishes embryonic stem cells from adult stem cells found in adults; while embryonic stem cells can generate all cell types in the body, adult stem cells are multipotent and can produce only a limited number of cell types. If the pluripotent differentiation potential of embryonic stem cells could be harnessed in vitro, it might be a means of deriving cell or tissue types virtually to order. This would provide a radical new treatment approach to a wide variety of conditions where age, disease, or trauma has led to tissue damage or dysfunction.

Additionally, under defined conditions, embryonic stem cells are capable of propagating themselves indefinitely in an undifferentiated state and have the capacity when provided with the appropriate signals to differentiate, presumably via the formation of precursor cells, to almost all mature cell phenotypes.[6] This allows embryonic stem cells to be employed as useful tools for both research and regenerative medicine, because they can produce limitless numbers of themselves for continued research or clinical use.

Because of their plasticity and potentially unlimited capacity for self-renewal, Embryonic stem cell therapies have been proposed for regenerative medicine and tissue replacement after injury or disease. Diseases that could potentially be treated by pluripotent stem cells include a number of blood and immune-system related genetic diseases, cancers, and disorders; juvenile diabetes; Parkinson's; blindness and spinal cord injuries. Besides the ethical concerns of stem cell therapy (see stem cell controversy), there is a technical problem of graft-versus-host disease associated with allogeneic stem cell transplantation. However, these problems associated with histocompatibility may be solved using autologous donor adult stem cells, therapeutic cloning. The therapeutic cloning done by a method called somatic cell nuclear transfer (SCNT) may be advantageous against mitochondrial DNA (mtDNA) mutated diseases.[7] Stem cell banks or more recently by reprogramming of somatic cells with defined factors (e.g. induced pluripotent stem cells). Embryonic stem cells provide hope that it will be possible to overcome the problems of donor tissue shortage and also, by making the cells immunocompatible with the recipient. Other potential uses of embryonic stem cells include investigation of early human development, study of genetic disease and as in vitro systems for toxicology testing.

According to a 2002 article in PNAS, "Human embryonic stem cells have the potential to differentiate into various cell types, and, thus, may be useful as a source of cells for transplantation or tissue engineering."[8]

Current research focuses on differentiating ES into a variety of cell types for eventual use as cell replacement therapies (CRTs). Some of the cell types that have or are currently being developed include cardiomyocytes (CM), neurons, hepatocytes, bone marrow cells, islet cells and endothelial cells.[9] However, the derivation of such cell types from ESs is not without obstacles and hence current research is focused on overcoming these barriers. For example, studies are underway to differentiate ES in to tissue specific CMs and to eradicate their immature properties that distinguish them from adult CMs.[10] Lately,two teams in San Diegos ViaCyte and Bostons Harvard University successively announced their progress on embryonic stem cells for curing diabetes, which was suggested to be the beginning of the golden age of stem cell therapeutics.[11]

Besides in the future becoming an important alternative to organ transplants, ES are also being used in field of toxicology and as cellular screens to uncover new chemical entities (NCEs) that can be developed as small molecule drugs. Studies have shown that cardiomyocytes derived from ES are validated in vitro models to test drug responses and predict toxicity profiles.[9] ES derived cardiomyocytes have been shown to respond to pharmacological stimuli and hence can be used to assess cardiotoxicity like Torsades de Pointes.[12]

ES-derived hepatocytes are also useful models that could be used in the preclinical stages of drug discovery. However, the development of hepatocytes from ES has proven to be challenging and this hinders the ability to test drug metabolism. Therefore, current research is focusing on establishing fully functional ES-derived hepatocytes with stable phase I and II enzyme activity.[13]

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Embryonic stem cell - Wikipedia, the free encyclopedia

iPSC are derived from skin or blood cells that have been reprogrammed back into an embryonic-like pluripotent state that enables the development of an unlimited source of any type of human cell needed for therapeutic purposes. For example, iPSC can be prodded into becoming beta islet cells to treat diabetes, blood cells to create new blood free of cancer cells for a leukemia patient, or neurons to treat neurological disorders

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Induced Pluripotent Stem Cells (iPS) | UCLA Broad Stem ...

Induced stem cells (iSC) are stem cells artificially derived from somatic, reproductive, pluripotent or other cell types by deliberate epigenetic reprogramming.

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Induced stem cells - Wikipedia, the free encyclopedia

Volume 11, Issue 5, October 2013, Pages 299303 Special Issue: Induced Pluripotent Stem Cells Edited By Qi Zhou Induced pluripotent stem (iPS) cells can be generated by forced expression of four pluripotency factors in somatic cells.

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Pluripotency of Induced Pluripotent Stem Cells

Our center is a research affiliate of Cell Surgical Network (CSN). Carolina Stem Cell uses adipose derived mesenchymal stem cells for deployment & clinical research. Early stem cell research has traditionally been associated with the controversial use of embryonic stem cells

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Stem Cell Clinic

Helga Kolb

1. General characteristics.

Amacrine cells of the vertebrate retina are interneurons that interact at the second synaptic level of the vertically direct pathways consisting of the photoreceptor-bipolar-ganglion cell chain. They are synaptically active in the inner plexiform layer (IPL) and serve to integrate, modulate and interpose a temporal domain to the visual message presented to the ganglion cell. Amacrine cells are so named because they are nerve cells thought to lack an axon (Cajal, 1892). Today we know that certain large field amacrine cells of the vertebrate retina can have long axon-like processes which probably function as true axons in the sense that they are output fibers of the cell (see later section on dopaminergic amacrine cells). However these amacrine axons remain within the retina and do not leave the retina in the optic nerve as do the ganglion cell axons. Figure 1 shows one of the earliest depictions of the retinal cell types including amacrine cells drawn by Ramon y Cajal (circa 1890). These retinal cell types were visualized using the anatomical silver impregnation method devised by the Italian anatomist Camillo Golgi in the nineteenth century (Fig. 2).

Fig. 1. Drawing of the retina made by Cajal

Since the time of Cajal we have known that amacrine cells come in all shapes, sizes and stratification patterns. Since those days many more morphological subtypes have and continue to be described from further Golgi studies, intracellular recordings and immunocytochemical staining. Thus, we presently have a classification of amacrine cells consisting of about 40 different morphological subtypes.

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Roles of Amacrine Cells by Helga Kolb Webvision

Biologists estimate that there are about 5 to 100 million species of organisms living on Earth today. Evidence from morphological, biochemical, and gene sequence data suggests that all organisms on Earth are genetically related, and the genealogical relationships of living things can be represented by a vast evolutionary tree, the Tree of Life. The Tree of Life then represents the phylogeny of organisms, i. e., the history of organismal lineages as they change through time. It implies that different species arise from previous forms via descent, and that all organisms, from the smallest microbe to the largest plants and vertebrates, are connected by the passage of genes along the branches of the phylogenetic tree that links all of Life (Figure 1).

Figure 1: All organisms are connected by the passage of genes along the branches of the phylogenetic Tree of Life.

The organisms that are alive today are but the leaves of this giant tree, and if we could trace their history back down the branches of the Tree of Life, we would encounter their ancestors, which lived thousands or millions or hundreds of millions of years ago (Figure 2).

Figure 2: Living organisms sit like leaves at the tips of the branches of the Tree of Life. Their evolutionary history is represented by a series of ancestors which are shared hierarchically by different subsets of the organisms that are alive today.

The notion that all of life is genetically connected via a vast phylogenetic tree is one of the most romantic notions to come out of science. How wonderful to think of the common ancestor of humans and beetles. This organism most likely was some kind of a worm. At some point this ancestral worm species divided into two separate worm species, which then divided again and again, each division (or speciation) resulting in new, independently evolving lineages. Little did these worms know, those hundreds of million years ago, that some of their number would end up evolving into beetles, while their brothers and sisters would end up as humans or giraffes.

Organisms have evolved through the ages from ancestral forms into more derived forms. New lineages generally retain many of their ancestral features, which are then gradually modified and supplemented with novel traits that help them to better adjust to the environment they live in. Studying the phylogeny of organisms can help us explain similarities and differences among plants, animals, and microorganisms. The Tree of Life thus provides a rigorous framework to guide research in all biological subdisciplines, and it is therefore an ideal model for the organization of biological knowledge.

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TOLweb: what is phylogeny? - Tree of Life Web Project

1. Rommens JR, Iannuzzi MC, Kerem BS et al: Identification of the cystic fibrosis gene: chromosomal walking and jumping. Science 245:1059, 1989

2. Hall JM, Friedman L, Guenther C et al: Closing in on a breast cancer gene on chromosome 17q. Am J Hum Genet 50:1235, 1992

3. Easton DF, Bishop DT, Ford D et al: The Breast Cancer Linkage Consortium: Genetic linkage analysis in a familial breast and ovarian cancer: results from 214 families. Am J Hum Genet 52:678, 1993

4. Fishel R, Loscoe MK, Rao MRS et al: The human mutator gene homolog MSH2 and its association with hereditary polyposis colon cancer. Cell 75:1027, 1993

5. The Huntington's Disease Collaborative Research Group: A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72:971, 1993

6. Saunders AM, Strittmatter WJ, Schmechel D et al: Association of apolipoprotein E allele e4 with late-onset familial and sporadic Alzheimer's disease. Neurology 43:1467, 1993

7. Frezal J, Abule MS, De Fougerolle T: Gene atlas: A catalogue of mapped genes and other markers, 2nd ed, p 1013. Paris, Inserm/John Libbey, 1991

8. Frezal J, Kaplan J, Dolifus H: Mapping the eye diseases. Ophthalmic Paediatr Genet 13:37, 1992

9. Musarella MA: Gene mapping of ocular diseases. Surv Ophthalmol 36:285, 1992

10. Jay B, Jay M: Molecular genetics in clinical ophthalmology. In Davidson SI, Jany B (eds): Recent Advances in Ophthalmology, Vol 8, pp 185206. New York, Churchill Livingstone, 1992

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Foundation Volume 3, Chapter 55. Molecular Genetic Basis ...

Abstract

Our understanding of the development of the retina and visual pathways has seen enormous advances during the past 25years. New imaging technologies, coupled with advances in molecular biology, have permitted a fuller appreciation of the histotypical events associated with proliferation, fate determination, migration, differentiation, pathway navigation, target innervation, synaptogenesis and cell death, and in many instances, in understanding the genetic, molecular, cellular and activity-dependent mechanisms underlying those developmental changes. The present review considers those advances associated with the lineal relationships between retinal nerve cells, the production of retinal nerve cell diversity, the migration, patterning and differentiation of different types of retinal nerve cells, the determinants of the decussation pattern at the optic chiasm, the formation of the retinotopic map, and the establishment of ocular domains within the thalamus.

In 1986, when Vision Research published its 25th Anniversary Issue, there was no chapter dedicated to developmental visual anatomy, being the summary descriptor provided by the editors for the present chapter. The closest coverage was provided within a chapter on visual development, focusing upon the acquisition of visual function, the consequences of early visual deprivation or restricted visual exposure, and on the associated plasticity within visual cortex ( Teller & Movshon, 1986). It is interesting to re-visit that historical overview now, 25years later, to appreciate the excitement within the field during those golden years of visual neurophysiology. Three pioneers in our understanding of the development of the visual system received the Nobel Prize in Physiology or Medicine during that era, in 1981, Roger Sperry, David Hubel and Torsten Wiesel, and the contributions of two of them feature prominently within that article. As acknowledged by the authors, In 1960, the neurobiology of visual development was dominated by the work of Roger Sperry. But rather than this being the prelude to a tribute, Sperry is taken to task for his preoccupation with the hard-wiring of the visual pathway, and his impact for the era under review was largely dismissed: Sperrys relentless emphasis on the independence of neural development from neural function in the developing animal was to have a short life after 1961 (p. 1486, original italics).

Since that anniversary issue in 1986, the past 25years have witnessed unprecedented experimental as well as conceptual advances in our understanding of the development of the retina and sub-cortical visual pathways, much of it occurring well before the onset of visual function. Many of these advances vindicate a hard-wiring perspective such as Sperrys, relying upon cell-signaling interactions independent of neural transmission, while others show that neural function long before the onset of photo-transduction plays a critical role in the formation of neural circuitry. The phenomenal scientific pace of the past 25years has been made possible largely by new technologies that continue to expand the front of developmental neurobiology in general. The experimental advances have been a consequence of the revolution in molecular biology and by the availability of new imaging technologies, permitting genetic dissection of the molecular factors and cellular interactions underlying retinal and optic pathway development, and the visualization of single neurons or populations of cells as they pass through the cell cycle, express transcription factors and the downstream genes they regulate, migrate to their specific layers, differentiate their characteristic morphologies, navigate an axonal trajectory to central visual structures, establish and refine their synaptic connections, and undergo programmed cell death. The present review will not consider in detail those technical advances themselves; the reader is directed to another recent colorful review providing ample coverage of this ever-expanding toolbox (Mason, 2009). The consequent experimental results have led to new conceptual insights, altering the ways in which we think about retinal development and target innervation, and the present focus will be upon these changes in our understanding.

One should not fault the myopia of the former review too much; without a doubt, we simply could not appreciate the full nature of the neurobiological issues at play 25years ago.1 Visual cortex was where the action was, and electrophysiology was the tool of choice for understanding the mechanics underlying visual function. We now know so much more about the pre-visual development of the retina and sub-cortical visual pathways, from a decidedly cellular and molecular biological perspective, that I will restrict the present coverage accordingly, and unashamedly, as vision will hardly be mentioned.

By comparison with the other chapters in this special issue of Vision Research, the purview of the present chapter is vast, encompassing advances not only in our understanding of the various components establishing the complex architecture and connectivity of the neural retina, but also of the visual pathways and their innervation of target visual structures. Any such review of strides taken over a defined period of time must to some extent be idiosyncratic (as in that former paper), but I believe these issues largely summarize the major conceptual and experimental advances during the past 25years. I have chosen to highlight eight issues, briefly recapitulating these advances and sacrificing much detail due to space limitations. Each of these topics has been reviewed in far greater detail elsewhere, and doubtless researchers working on development of the visual system will find reason enough to feel frustrated by the brevity of the present effort. Rather, my intended audience has been that collection of vision researchers that digest the literature on retinal and pathway development with only modest fervor, to give them a synopsis of the major advances during this era, as well as current students and post-docs working within this field of developmental neurobiology that may not appreciate the degree to which this field has advanced. The latter group need only compare the coverage of the developing retina and visual pathway provided by textbooks then in use (e.g. Jacobson, 1978andPurves and Lichtman, 1985) with that provided more recently ( Sanes, Reh, & Harris, 2006) to appreciate the remarkable evolution in our understanding of these developmental processes. The former textbooks reflect the strong foundations of the field drawn from experimental embryology and neurophysiology but now seem sadly deficient in providing much account of the histotypical interactions between cells or of the genes expressed and molecular signals they set in motion that participate in these events.

Twenty-five years ago, while we had some appreciation that an early eye field was derived from the neural plate and was critical for the development of the retina, we had no knowledge of the transcriptional control of this process by a handful of early eye-field genes that are now understood to command a downstream cascade of genes critical for assembling the mature retina (Zuber & Harris, 2006). As the eye cup emerges and expands in size, the factors modulating cell cycle kinetics have been dissected with increasing detail, including the molecular mechanisms driving interkinetic nuclear translocation, the intracellular and extracellular determinants of cell-cycle exit, and the factors that coordinate the wave of neurogenesis progressing from its site of initiation (Agathocleous and Harris, 2009, Baye and Link, 2007, Del Bene et al., 2008, Dyer and Cepko, 2001, Levine and Green, 2004, Martins and Pearson, 2008andNorden et al., 2009). The present coverage will begin with the emerging neural retina at the outset of neurogenesis, considering advances in our understanding of the lineage relationships between retinal neurons, the determination of neuronal cell-types and the production of species-specific retinal architecture, the control of neuronal positioning, and the determinants of morphological differentiation.

Retinal progenitors were understood to expand the pool of post-mitotic precursor cells that would ultimately adopt various cellular fates, but there was no firm understanding of whether dedicated progenitors yielded particular types of cell, or if progenitors were multi-potent. While birth-dating studies had already shown that each type of retinal nerve cell was born in a distinct window during retinal neurogenesis (Carter-Dawson and LaVail, 1979, Drger, 1985, Hinds and Hinds, 1979, Sidman, 1961andYoung, 1985), these provided no insight into the clonal relationships between the cells of the retina. In the late 1980s, two different approaches were employed to label single retinal progenitor cells in order to identify their progeny at subsequent stages of maturity. One was to inject single cells with cytoplasmic tracers that would remain detectable within progeny despite progressive dilution following repeated cell divisions (Holt et al., 1988andWetts and Fraser, 1988). The other was to use replication-deficient retroviruses encoding reporter genes to infect single cells, therein bypassing the problem of progressive dilution with repeated mitoses (Turner and Cepko, 1987andTurner et al., 1990). Both approaches yielded comparable findings that retinal progenitor cells were in fact multi-potent, producing clones of cells that included a variety of retinal neuronal types as well as Mller glia. They lacked, however, any retinal astrocytes, handily accounted for, at roughly the same time, by the demonstration that astrocytes are immigrants to the neural retina, being derived from a distinct progenitor cell in the optic stalk and migrating into the inner retina during the period of retinal neurogenesis (Ling and Stone, 1988, Stone and Dreher, 1987andWatanabe and Raff, 1988).

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Development of the retina and optic pathway - ScienceDirect

B2mtm1Unc related

Adoro S; Erman B; Sarafova SD; Van Laethem F; Park JH; Feigenbaum L; Singer A. 2008. Targeting CD4 coreceptor expression to postselection thymocytes reveals that CD4/CD8 lineage choice is neither error-prone nor stochastic. J Immunol 181(10):6975-83. [PubMed: 18981117] [MGI Ref ID J:140942]

Adoro S; McCaughtry T; Erman B; Alag A; Van Laethem F; Park JH; Tai X; Kimura M; Wang L; Grinberg A; Kubo M; Bosselut R; Love P; Singer A. 2011. Coreceptor gene imprinting governs thymocyte lineage fate. EMBO J 31(2):366-77. [PubMed: 22036949] [MGI Ref ID J:180236]

Agerstam H; Jaras M; Andersson A; Johnels P; Hansen N; Lassen C; Rissler M; Gisselsson D; Olofsson T; Richter J; Fan X; Ehinger M; Fioretos T. 2010. Modeling the human 8p11-myeloproliferative syndrome in immunodeficient mice. Blood 116(12):2103-11. [PubMed: 20554971] [MGI Ref ID J:164507]

Aguado E; Richelme S; Nunez-Cruz S; Miazek A; Mura AM; Richelme M; Guo XJ; Sainty D; He HT; Malissen B; Malissen M. 2002. Induction of T helper type 2 immunity by a point mutation in the LAT adaptor. Science 296(5575):2036-40. [PubMed: 12065839] [MGI Ref ID J:77098]

Albu DI; Vanvalkenburgh J; Morin N; Califano D; Jenkins NA; Copeland NG; Liu P; Avram D. 2011. Transcription factor Bcl11b controls selection of invariant natural killer T-cells by regulating glycolipid presentation in double-positive thymocytes. Proc Natl Acad Sci U S A 108(15):6211-6. [PubMed: 21444811] [MGI Ref ID J:171277]

Aldrich CJ; Ljunggren HG; Van Kaer L; Ashton-Rickardt PG; Tonegawa S; Forman J. 1994. Positive selection of self- and alloreactive CD8+ T cells in Tap-1 mutant mice. Proc Natl Acad Sci U S A 91(14):6525-8. [PubMed: 8022816] [MGI Ref ID J:19192]

Alli R; Nguyen P; Boyd K; Sundberg JP; Geiger TL. 2012. A mouse model of clonal CD8+ T lymphocyte-mediated alopecia areata progressing to alopecia universalis. J Immunol 188(1):477-86. [PubMed: 22116824] [MGI Ref ID J:180590]

Alsharifi M; Lobigs M; Simon MM; Kersten A; Muller K; Koskinen A; Lee E; Mullbacher A. 2006. NK cell-mediated immunopathology during an acute viral infection of the CNS. Eur J Immunol 36(4):887-96. [PubMed: 16541469] [MGI Ref ID J:114787]

Antal Z; Baker JC; Smith C; Jarchum I; Babad J; Mukherjee G; Yang Y; Sidney J; Sette A; Santamaria P; DiLorenzo TP. 2012. Beyond HLA-A*0201: new HLA-transgenic nonobese diabetic mouse models of type 1 diabetes identify the insulin C-peptide as a rich source of CD8+ T cell epitopes. J Immunol 188(11):5766-75. [PubMed: 22539795] [MGI Ref ID J:188404]

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