Biology p348-369 X Chromosome Inactivation & Gene Expression

• Mammalian development starts with a single zygote, leading to all tissues and organs in a mature organism.
• The organization and transformation of cells during development depend on precise signalling
• Asymmetrical cell division, cell signalling, migration, gene expression, and programmed cell death work together for embryo patterning.

Cell Potency

• A zygote is totipotent, it can give rise to every cell type.
• With asymmetrical cell division during cleavage, blastomeres become progressively restricted beyond the 8-cell stage.
• Blastomeres become restricted to either embryonic or extraembryonic cell types as the embryo progresses toward blastulation and are then considered pluripotent.
• Trophoblast cells are restricted to extraembryonic fates, unable to become part of the embryo itself near blastocyst stage.
• Cells of the neural tube are considered multipotent at neural tube closure and allow them to generate multiple cell types within a restricted population or lineage
• Multipotent cells may become further restricted, leading to unipotent cells that generate one cell type.
• Terminal differentiation leads to unique cell types with biochemical signatures, structures, and functions through differential gene expression.
• Stem cells retain potency and division ability while producing daughter cells that terminally differentiate into specific cell types.
• Stem cells are found in adult tissues like bone marrow and brain, beyond just embryonic development.
• Some stem cell populations self-renew.
• In asymmetrical cell division, one daughter cell may terminally differentiate, while the other maintains stem cell properties to maintain the progenitor cell pool.
• Unipotent spermatogonial stem cells produce daughter cells during spermatogenesis and differentiate into primary spermatocytes or maintain the stem cell population.
• Committed cells progress through stages, eventually being tied to a specific cell fate.
• Totipotent cells are unspecified initially.
• Cell specification begins early in development when cells can differentiate into a particular cell type in a neutral environment, but can be changed via external cues at this stage.
• Cells are determined when they are tied to a specific fate, unchangeable even in alternate environments.
• Progenitor cells undergo terminal differentiation after determination, developing specialized structures and functions and may also leave the cell cycle.

Gene Regulation

• Differential gene expression, influenced by intrinsic and extrinsic factors, directs determination and differentiation of unique cell types.
• Early embryogenesis relies on intrinsic factors while later patterning involves extrinsic factors, which results in progressive cell fate restriction.
• During the early cleavage stage of embryogenesis, cell division is rapid, relying on oocyte stores of mRNA and proteins
• The embryonic genome becomes active at the 4- to 8-cell stage, while oocyte contributions persist through blastocyst stage.
• Before genome activation, the embryonic genome undergoes extensive epigenetic remodeling for transcription factors to access chromatin, thus regulating embryonic gene expression.
• During remodeling, cytosine nucleotides may be methylated, generally silencing gene expression, however, for certain genes, maternal and paternal methylation patterns remain intact, leading to parent-specific gene expression, known as genomic imprinting.
• When the paternal allele is imprinted (methylated), only the maternal allele leads to gene expression and vice versa.
• XX individuals compensate for having twice as many X chromosome genes compared to XY individuals through X chromosome inactivation.
• During X inactivation, XIST gene expression inactivates one X chromosome in each cell, initiating epigenetic modifications like chromatin remodeling, DNA methylation, and gene silencing
• The X chromosome expressing XIST condenses into a Barr body.
• X chromosome inactivation is random, with each cell expressing either the maternal or paternal X chromosome. Expression is roughly half of the individual's cells and is used if an XX individual is heterozygous for an X-linked trait
• Regulatory elements outside of DNA coding regions, when bound by transcription factors, enhance gene expression levels.
• Tissue-specific gene expression arises due to unique combinations of transcription factors expressed in cells during development.
• Enhancer sequences will regulate a single gene's expression in different tissues/times of development. Only specific combinations of transcription factors bound to an enhancer allow gene expression in a particular cell type, otherwise the gene remains unexpressed.
• The transcription factor PTF1A is expressed in pancreatic and cerebellar progenitor cells, controlled by two distinct regulatory enhancers

Cell Signalling and migration

• Gene mutations within enhancer sequences disrupt development in a tissue-specific fashion.
• Cell-cell signaling drives many developmental activities like division, adhesion, migration, and differentiation.
• Ectodermal cells are induced to become neural plate cells in response to notochord signal secretion.
• Induction involves cells or tissues secreting signaling molecules (inducers) and responding cells or tissues that are competent.
• Secreted paracrine signals effect nearby cells via diffusion, autocrine signals effect the same cell and juxtacrine signals effect neighbouring signals, unlike endocrine signaling development before circulatory systems
• Inductive interactions often are reciprocal.
• Vertebrate eye development requires ectoderm overlaying the vesicle induces lens formation, while lens cells instruct vesicle to retina.
• Signaling gradients are essential for early embryonic development.
• Morphogens are inductive paracrine factors diffusing from a signaling cell, forming a concentration gradient within nearby tissues.
• Fates of receiving cells are affected by the concentration of morphogen to which they are exposed and morphogen gradients are also influenced by time-dependent destruction and/or uptake into cells.
• Overlapping morphogen gradients may be used to create expression and differentiation patterns during development.
• For example, morphogen concentration affects the differentiation of spinal neurons along the dorsal-ventral axis
• Opposing morphogen concentrations of BMP, Wnt, and sonic hedgehog (Shh) in the neural tube specify dorsal and ventral cell fates, with more BMP/Wnt secreted from ectoderm while more Shh secreted by notochord.
• The Notch pathway is a juxtacrine signaling pathway crucial in developmental biology.
• The Notch pathway uses a Notch receptor protein in an inducing cell interating with a ligand, which induces differentiation of one progenitor cell while keeping its neighbour undifferentiated, also known as Lateral inhibition
• Cells must migrate short and long distances as development proceeds.
• Cells migrate by responding to environmental/surrounding signals.
• Neural crest cell migration involves cells losing adhesive junctions and separating from the epithelium through delamination.

Programmed Cell Death

• Normal development generates excess cell numbers that are removed through apoptosis.
• Mammalian development includes apoptosis during blastocyst formation, shaping of tubular structures, and separating digits.
• During vertebrate limb development, digits are specified by signalling gradients from the posterior interdigital tissue, whereas apoptosis of the interdigital webbing is induced after digit formation.
• Environmental factors, particularly those impacting nutrients can have major impacts to development
• Folate deficiencies leads to disrupted folic acid metabolism and may affect DNA methylation in the developing nervous system.
• Approx 25-30% in humans is preventable by taking more folate.

Gestation

• Gestation typically lasts 38 weeks from ovulation to birth, expressed as 40 weeks from the last menstrual cycle.
• There are many maternal changes that occur, divided into 3 trimesters.
• The first trimester (weeks 1-12) includes fertilization, implantation, embryonic period, and start of fetal period.
• Second trimester (weeks 13-26) includes full placenta formation and pregnancy hormone secretion.
• The third trimester begins at week 27 and ends until the end of pregnancy (weeks 38-40).
• Fetus and maternal materials are exchanged through the placenta (connected to the umbilical cord).
• Maternal blood does not mix with the fetal blood, instead diffusion occurs through the small chorionic villi.
• Fetal red blood cells have the specialized hemoglobin F, which has greater 02 affinity than hemoglobin A, thereby favoring 02 transfer.
• Oxygen and nutrients are transported from a uterine artery into the intervillous space, diffusing into fetal capillaries linked to the umbilical vein.
• Carbon dioxide and wastes from are transported via a pair of umbilical arteries to the placenta, diffusing into the intervillous space and the uterine vein.
• The placenta acts as a protective barrier however certain pathogens and immunoglobulins (antibodies) can still cross
• The lungs oxygenate blood from the fetus in the placenta in a pulmonary circulation manner.
• Oxygenated fetal blood returns via the umbilical cord via a single umbilical vein, as deoxygenated blood is sent via two umbilical aa.
• Oxygenated blood enters the umbilical vein then enters the ductus venosus to bypass liver and connect with inferior vena cava (since lungs and liver are not fully functioning)
• Veins mix blood for return to right atrum. This occurs through the foramen ovale, and then to the aorta
• A small portion of passes to ventricle, then pulmonary trunk, then directly with the ascending aorta via the ductus arteriosus. This is deoxygenated blood that mixes and flows towards the lower body and is transported via the 2 umbilical AA to the placenta
• The labor process (parturition) is triggered by mechanisms that depend on both maternal and fetal signals, where the fetus exits the uterus through the vagina.
• pressure on increases impulses to neurosecretory, resulting in the hormone oxytocin. Then oxytocin leads to contractions through prostaglandins in the myometrium, and the cycle continues in a positive feedback loop. When the cervix releases the tension, the process is broken.
• Labour lasts 10 cm, broken down in three stages: onset of regular uterine contractions, Expulsion through birth canal within minutes, lastly delivery of placenta

Lactation

• After childbirth infant relies for nutrition to external sources.
• Breast develop influence of estrogen, but is mainly milk producing from mammary glands developing further.
• Glands are composed of lobes, which secrete milk when they are stimulated.
• Before delivery, high estrogen and progesterone in the mammary glands result in small amounts of colostrum.
• Later, the mammory glands produce more milk with prolactin and other hormones.
• Also provide to passive immunity to the infant.

Tissue Regeneration and Senescence

• Organisms can repair damage but can not restore some damage.
• The potency of adult stem cells is much more restricted than the potency of embryonic stem cells
• Tissues posses regeneration but decreases with time
• Adult stem cells assist for repair
• Regeneration involves cell reproduction
• Senescent cells secrete substances related to stress
• Cells are terminated through apoptosis
• Long term effects are related to cancerous activities that accumulate with time.

Explore X chromosome inactivation in XX individuals, focusing on the gene responsible for initiating it and epigenetic modifications. Learn about the role of transcription factors in tissue-specific gene expression during development.