Mammalian Immune System
The mammalian immune system is comprised of the innate and adaptive immune systems. The innate immune system is the first line of defense and usually begins when a pathogen infects a cell. Cells can identify pathogens using proteins like pattern recognition receptors. The innate immune system in non-specific, meaning it will attack all foreign invaders the same way. The adaptive immune system is initiated when dendritic cells that capture pathogens during innate responses present their proteins to T-cells. The adaptive immune system is comprised of B-cells and T-cells. Both cell types develop in the bone marrow initially. B-cells mature in the bone marrow and travel into the periphery as naive cells until they are activated to fully mature. T-cells undergo partial development in the bone marrow and then are transferred to the thymus to undergo further differentiation. T-cells that react to proteins in your own body will be removed from the thymus. The T-cells that get through the thymus are fully develop and flow to the periphery to be activated.
B-cells are lymphocytes produced in the bone marrow (hence “B” cell) that are primarily responsible for the production of antibodies as a means to fight an infection. These cells contain receptors which are integral membrane proteins that bind to specific antigens. Once they are bound to the antigens, the B-cells engulf and digest the antigen and are then stimulated to enter the cell cycle. This entrance into the cell cycle (and subsequent division) leads to the production of more B-cells with identical specificity towards antigens or the differentiation into plasma cells which will produce antibodies. B-cells have the ability to form Memory B-cells, which can live for a very long time and respond very quickly to repeated infections, increasing the likelihood of the organism’s survival.
T-cells are a subgroup of a group of white blood cells called lymphocytes. T-cells play an essential role in cell-mediated immunity.
More information on RUNX protein and its role in T-cell Development
More Information of the importance of Foxp3 in T-cell gene regulation
T-cells originate from hematopoietic stem cells in the bone marrow and development in the thymus via three processes: beta-selection, positive selection, and negative selection.
When T-cell precursors begin to express c-kit and CD44, they become known as DN1 thymocytes. At this stage, there is rearrangement of T-cell receptor genes through somatic recombination. This allows for increasing T-cell specificity, providing a defense against rapidly evolving pathogens. This rearrangement occurs in two steps. First, The TCRβ chain is rearranged and then, it is paired with the pre-Tα to produce the pre-TCR. The DN1 cell becomes a DN2 cell. The DN2 cell starts expressing CD3 and stops expressing c-kit and CD44. It becomes a DN3 cell. Beta-selection checkpoint eliminates cells with non-functional T-cell receptors. Cells that have produced functional pre-TCR can develop beyond DN3, but those who have been unable to produce pre-TCR die via PCD. Cells that pass beta-selection will cease expressing CD25, and will start to express CD4 and CD8.
The earliest T-cells express neither CD4 nor CD8. During development, maturing T-cells move into the thymic cortex where they interact with MHC peptide complexes of the thymic cortical epithelial cells. These T-cells express CD4, CD8, and a T-cell receptor. A cell with a receptor able to recognize an MHC class I molecule receives signals on survival and maturation, and eventually begins to only express CD8. When cells with a receptor able to recognize an MHC class II molecule receives signals on survival and maturation, it eventually only expresses CD4. This is called positive selection. Cells who do not have receptors that recognize either MCH class I or class II molecules do not receive signals on survival and maturation, and therefore die via programmed cell death. (PCD). Cells that were able to recognize MCH peptide complexes too easily also receive signals causing them to undergo PCD.
Next, cells travel to the medulla. Here, negative selection occurs. If cells interact too strongly with the self-antigen they receive signals to undergo programmed cell death. This is to prevent the formation of self-reactive T-cells. The matured CD4 and CD8 T-cells exit the thymus.
Mouse Embryo Development
The fetus of a mouse develops in about 3 weeks.
Overview of mammalian embryonic development: Human embryo development on YouTube by HHMI
An evolutionary perspective on features of mammalian embryo development:
Mammalian Reproduction and Sex Determination
Breeding onset is at about 50 days of age for both males and females. Mice are polyestrous and breed year round; ovulation is spontaneous (females come into heat at fairly regular intervals, every 4-5 days, throughout the entire year until they are bred. The period in which a female mouse is receptive to the male and allows breeding is about 12 hours and occurs at night. Sexually mature mice must be properly paired to breed successfully. A single male mouse may be included in an enclosure with one or more female mice (the harem system) without difficulty. Including more than one male mouse in this situation can provoke fighting between males, who will try to compete for the right to mate with the females. Female mice can come back into heat within 14-28 hours after birthing a litter, which is called “postpartum estrus,” and means they can be nursing and pregnant at the same time. Pregnancy in mice lasts an average of 3 weeks but can be extended as much at 10 days longer if pregnant female is suckling a previous litter. Litter sizes average between 10-12 pups, but litter size is highly strain dependent. Generally, inbred mice tend to have longer gestation periods and smaller litters than outbred and hybrid mice. The young are called pups and weigh 0.5-1.5 grams at birth, are hairless, and have closed eyelids and ears. Cannibalism is uncommon, but females should not be disturbed during parturition and for at least 2 days postpartum. The first litter birthed is usually smaller in number, and litter sizes decrease as breeding females age.
Mammalian sex determination can be controlled by genes such as Sry, MIS, WT1, and SF1. More Information on Mammalian Sex Determination.
In addition to murine species, embryological studies have been expanded to primates. After fertilization, blastula cells face the decision to differentiate into either the inner cell mass (ICM) or the trophectoderm (TE). Studies have indicated that Banf-1, a Sox-2 associated protein, could play a potential role in how stem cells are maintained; namely, the decision between stem cell self-renewal and specialization. However, the effects of Banf-1 seem to differ between mice and primates, suggesting much variability in even the earliest stages of development amongst different mammalian species. In addition, the caudal-type homeoprotein CDX2 has been implicated in trophectoderm formation and development. The interactions of both Banf-1 and CDX2 with known transcription factors such as Oct4, Nanog, and Sox2 look promising in the quest to decipher the earliest factors affecting primate cell fate decision. More on ESC differentiation and trophectoderm development.
The trophectoderm, also known as the trophoblast layer, is involved in the attachment of the embryo to the maternal uterine lining and the formation of the mature placenta. A critical step in embryo implantation is the induction of apoptosis (or cell death) of the uterine epithelial cells. One of the layers of the trophoblast plays a role in this critical step, and cell death is required in order for the trophectoderm to properly invade the endometrium.
Signaling factors such as secreted frizzled-related protein 4 (sFRP4) have been studied in primates such as the macaque monkeys and humans. sFRP4 increases the incidence of apoptosis and shows potential to be a key signaling molecule in the regulation of the implantation of the embryo and the formation of the placenta. For more information on the role of sFRP4, go to Where do babies come from? – Placental development and embryo implantation in primates.
Signaling Genes in Mammalian Cell Development
All living cells communicate with their surroundings to elicit intracellular modifications. These cellular signals are sent and received through the cell’s receptors that are located on the semipermeable membrane of the cell. These receptors recognize molecules and react by sending the messages through the cell, allowing changes including cellular death, proliferation, or variable expression of expression of genes. In signal transduction, proteins cluster and cleave, activated pathways downstream and eventually are translocated into the nucleus to repress or stimulate expression of genes.
Differential expression of the following genes affect development of Bcells and T cells:
RAG1 and RAG2- encode for proteins Involved in V(D)J joining in B and T cell receptors
Notch: T cell fate from common myeloid progenitor
Marginal Zone B cell development
General embryology: neurogenesis, miogenesis, hematopoiesis, intestinal and pancreatic differentiation
See Notch signaling role in B-cell Development
Sonic HedgeHog: differentiation and proliferation of thymocytes;
T cell signaling, selection and commitment.
See more information on Sonic HedgeHog role in immune/embryology development
SOCS family proteins: These molecules control the function of transcriptional regulators, STAT
SOCS2: In conjunction with CIS regulates cytokine signaling by inhibition of STAT molecules
SOCS3: Inhibits JAK molecules to control cytokine signaling.
SOCS1: Controls JAK signaling.
Genes Involved in Development of B-cells and T-cells
Developing Hematopoietic System.” International Journal of Developmental Biology 54.6-7 (2010): 1175-188. International Journal of Developmental Biology. UBC Press, 2010. Web. 07 Apr. 2012. .
Puberty Initiation in Mammals
Puberty is a complexly coordinated biological process, marked by GnRH secretion that triggers signaling cascade and gonadal activations. Kisspeptin and NKB, neuropeptides in hypothalamic neurons, and their receptors play an important role in pulsatile GnRH secretion in primates that govern initiation of puberty.
Infertility in Primates
Infertility is multi-faceted problem with many causes, most of them genetic. Any gene or protein that plays a role in events from sperm maturation to embryo implantation can decrease fertility and the chances of a successful pregnancy. To learn more about the genes and proteins involved in infertility, click here.
Development of Cannabinoid 1 Receptor Protein and mRNA in Monkey Dorsolateral Prefrontral Cortex
The cannabinoid 1 receptor (CB1R) is highly expressed in the mature primate DLPFC and plays an important role in the development of cognitive functions reliant on the DLPFC. For example, the age-related improvements in performance on working memory tasks parallels the increase of CB1R-immunoreactivity axons. Detecting the developmental trajectories of the innervation density and laminar distribution pattern of CB1R-immunoreactivity structures is crucial in determining how developmental changes in CB1Rs might render DLPFC circuitry vulnerable to cannabis exposure.
Tissue Regeneration in Mammals
Although not as adept as amphibians or invertebrates some species and tissues are capable of regeneration. The mammalian liver is able to regenerate in most species, and some species have special adaptations that allow them to regenerate specific tissues, such as deer replacing their antlers. Rabbits are able to regenerate tissue in their ears to a much greater extent than in other mammals, and recently this ability has been discovered in a mouse strain called Murphy Roths Large.
Mammals, unlike some animals such as Axolotl amphibians, are only able to regenerate their digit-tips on fingers when considering what the extent of limb regeneration may be. In addition, humans are hindered furthermore given that they lose the ability to regenerate even digit-tips with age. Recent research has shed light on this unique characteristic to mammals by showing that no transdifferentiation between lineages occurs, and there is regeneration derived specifically from lineage-restricted cells in mice as shown here:
Tissue Regeneration in Humans
Why does regeneration occur?
- Tissue regeneration is the process of renewal and growth of tissues and it is mainly common in limb development in organisms. Tissue engineering, the use of a combination of cells, engineering and materials methods, and biochemical and physio-chemical factors to replace or improve biological functions, is a growing field of research in today’s scientific world.
Watch this video to know more about regeneration--
Human Embryonic Stem Cells (hESC)
Human embryonic stem cells (hESC) are known for their self-renewal ability due to their pluripotency. HESC are derived from the blastocyst. In the inner cell membrane (which contains Oct 3/4), the cells retain the properties of self-renewal. These hESC can give rise to all germ layers, ectoderm, mesoderm and endoderm. There is great potential for these pluripotent hESC that can differentiate into most cell lineages. Many studies have been devotes into tissue and cell therapy. Other research goes into regenerating skin, cardiac and even neural cells. Some pathways that are involve in hESC differentiation include Activin/Nodal, BMP, FGF and Wnt. These signals are very crucial for neural induction.
Neural Induction involves the creation of the neural plate. In order for the ectoderm to differentiate to the neuroectoderm, the mesoderm must send a variety of signals (some of which are specified above).
The use of human embryonic stem cells has always been a topic of controversy. Despite the fact that these cells have the potential to treat many ailments and repair DNA damage, many people feel that using an embryo constitutes as murder. HESC are considered very useful for nervous system therapies but without general public support, research in this field will be limited.
Mammalian Tooth Development
Tooth development, which starts from embryonic stem cells within the mouth, occurs in most mammals. In mice specifically, tooth development is regulated by several genes, including bone morphogenetic protein 4, or Bmp4. Bmp4 is known to be regulated by the transcription factor Msx1. Recent research has indicated that another transcription factor, Tbx2, may also play a role in regulating the expression of Bmp4 during tooth development in mice. To learn more about the relationship between Bmp4, Msx1, and Tbx2, click here.