Human Developmental Biology. Danton Inc. O'Day
of time. Similarly older men can also produce sperm with abnormal chromosome numbers. This “paternal age effect” however cannot be due to meiotic block since it doesn’t occur in males.
Trisomy 21—Down Syndrome
Down syndrome is probably the most well known result from non-disjunction. As a result, Down syndrome individuals have an extra chromosome 21, hence the syndrome is also known as trisomy 21. Trisomy 21 affects the development of brain, immune system, heart and skeleton. Mental retardation is the constant hallmark of Down syndrome and individuals will typically develop early onset Alzheimer’s disease. Physically Down syndrome individuals have a broad face with a flat nasal bridge, wide set eyes and epicanthic folds (a skin fold on the upper eyelid). They also show a transverse crease in the palms of their hands. Often called a “simian crease”, the term is falling out of favor since “simian” refers to monkey or ape. Down syndrome occurs about once in every 700 births making it a common occurrence.
Down Syndrome at the Molecular Level
Trisomy 21 or Down syndrome is due to an extra copy of chromosome 21. Since these individuals have extra copies of certain genes this usually results in an excess production of certain proteins. The extra genes on chromosome 21 have many other functions and effects that are not all related to Down syndrome. However, a partial understanding of Down syndrome has come from studies of the genes encoded on chromosome 21. One of these gene is DSCR1 (Down Syndrome Critical Region 1) which encodes an inhibitory protein. While the role of the inhibitory protein DSCR1 in neuronal development is just one aspect of Down syndrome it does serve to exemplify how our understanding of this syndrome as well as many diseases is progressing
Figure 4.3. The role of DSCR1 in regulating gene expression during brain neuron development.
Figure 4.3 summarizes the role of DSCR1 in neuronal development. NFATc (Nuclear Factor of Activated T cells) is phosphorylated in the cytoplasm of nerve cells. In this state, NFATc cannot enter the nucleus. During the normal development of neurons, calcineurin (CN), a protein phosphatase, removes phosphate groups (i.e., dephosphorylates) NFATc. Dephosphorylated NFATc now can enter the nucleus to regulate genes required for normal neuron development. DSCR1 protein is an inhibitor of CN which exists in normal neurons but at a level where it doesn’t negatively affect the normal events of NFATc dephosphorylation.
As discussed previously, the gene DSCR1 is found on chromosome 21. The extra copy of chromosome 21 leads to over-expression of the CN inhibitor DSCR1 in developing brain cells (neurons) of Down syndrome individuals. These increased levels of DSCR1 lead to the inhibition of CN which in turn prevents it from dephosphorylating the critical transcription factor NFATc. Since phosphorylated NFATc can't enter the nucleus it can’t regulate specific genes required for normal brain development. As a result, neuronal development is inhibited in the brains of Down syndrome persons resulting in reduced cognitive ability.
Non-Disjunction: Monosomy—Turner Syndrome
While comparatively less common and less well-studied, Turner syndrome serves as a good example of monosomy. Individuals with Turner syndrome lack an X or Y sex chromosome due to non-disjunction. As a result these individuals have an XO genotype after fertilization. With only the X chromosome present, they exhibit a female phenotype. However due to the lack of certain genes, they are sterile. Physically these individuals have a short stature, webbed neck and high arched palate in their mouths. They also suffer from cognitive defects (i.e., affects learning). The syndrome is occurs once in about 2,500 individuals.
The Life of the Human Egg
The human egg goes through a series of starts and stops on its way to becoming prepared for fertilization and subsequently beginning development. The following diagram shows these events as they occur for a single egg (Figure 4.4). During embryonic development the PGCs increase in number by mitosis and migrate into the genital ridge where further mitosis occurs. As the embryo develops, the eggs will begin meiosis progressing to prophase I where they become arrested. At puberty, under the influence of hormones, some of the eggs will re-initiate meiosis and will be ovulated or will degenerate. The ovulated oocyte is arrested at metaphase II and will not continue meiosis unless activated by a sperm cell.
Figure 4.4. The life of a human egg from primordial germ cell to zygote.
Fertilization results in the completion of meiosis producing the female haploid pronucleus that will then fuse with the sperm pronucleus. The mechanisms whereby meiosis is arrested and restarted in other animals such as mice and frogs is an exciting area of research that involves signal transduction pathways and various kinases. Little has been done on this subject in human eggs. Remember, the majority of eggs remain locked in prophase I of meiosis during a female’s life. Each month only a few eggs are stimulated to move to meiosis II the rest remain in prophase I.
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