Developmental+and+Reproductive+Genetics

=**Objectives**=


 * 1. Review the genetic mechanisms that control how a cell differentiates from an embryonic (immature) cell into an adult cell that expresses a limited set of tissue-specific genes.** (p.665)

Two major processes control cellular differentiation: embryonic induction and cell sorting.

__Embryonic Inducion__ Fate of one embryonic region depends on recieving an extracellular signal froma second (usually adjacent) region. This is medated by growth factors and cell adhesion molecules (CAMs).

__Cell Sorting__ Embryonic cells posses specific surface determinants (CAMs) that permit similar cells to adhere to each other. These CAMs lead to specific aggregation and separation of cell populations.

All developmental processes eventually result in regulation of gene expression. In a differentiated cell, the cell cycle is usually switched off. Functional state is regulated by hormones through the reversible activation of specific structuarl genes. The remaning genome is normally irreversibly inactivated.


 * 2. Review the mechanism of programmed cell death (apoptosis).** (p.669)

After a fixed number of cell division, all cells become arrested in a terminally non-dividing state known as cellular senescence. These cells then undergo programmed cell death (apoptosis). Apoptosis is also an importnat process in normal development.


 * 3. Compare the major processes in embryonic development.** (p.669)

The major processes in embryonic development include axis specification, pattern formation, and organogenesis.

Axis specification determines the polarity/direction of the embryo, specifying the ventral/dorsal axis and the anterior/posterior axis.

Pattern formation describes as series of steps in which differentiated cells are arranged spatially to form tissues and organs. Interactions are mediated by the process of induction which occurs when cells of one embryonic region influence the organization and differentiation of cells in a second region.

Organogenesis involves many genes and associated proteins that form structures and provide signals to coordinate embryonic development.


 * 4. Review the various gene families associated with human development.** (p.670)

Establishment of the basic body plan is dependent on two major gene families: segmentation genes, and pattern formation genes.

Segmentation genes interact with one another ot subdivide the embryo into a linear series of progressively smaller but roughly similar segments.

Pattern formation genes assign a different developmental potential to each segment.


 * 5. Explain the function of homeotic, segmentation, zinc-finger, SOX, and signal transduction genes in human development.** (p.672, 676, 678-680)

__Homeotic Genes__ Homeotic genes share highly similar sequence called a homeobox. The homeobox sequence recognizes and binds to gene-regulatory regions and interacts with other DNA-binding proteins. Thus, they act as transcription factors that regulate the on/off of genes, providing different developmental paths for different embryonic segments.

A particular subgroup of homeobox genes are HOX genes which are important transcription factors that specify cell fate and establish regional axis. The temporal and spatial arrangement of HOX genes establish the anterior (3') and posterior (5') axis in fruit flies and mice. There are 4 clusters of HOX genes on 4 chromosomes, HOXA, HOXB, HOXC, and HOXD; each are numbered 1-13 even though not every cluster has 13 genes.

PAX genes are other homeobox-containing genes which code for transcription factors and are expressed mainly in nervous system but also in ear, eye, urogenital, limb bud, muscle, certain glands, and B-cell development.

__Segmentation__ Segmentation genes arrange the embryo into subdivided segments.

__Zinc-Finger Genes__ Gene products with the zinc-finger motif act as transcription factors through binding of the zing-finger to DNA. Errors in the //ZIC3// gene can result in errors in left/right laterality of internal organs.

__SOX Genes__ SRY-type HMG Box (SOX) genes show homology with the SRY gene (sex-determining region on y-chromosome). SOX genes regulate transcription and are expressed in specific tissues during embryogenesis. Errors indicate that SOX genes are not sex chromosome genems but are required to interact with SRY to allow normal sex differentiation.

__Signal Transduction Genes__ Most products are located on the inner side of the cell membrane where they receive signals from outside of the cell by activation of growth factor hormones for transmission into the nucleus.


 * 6. Review the various developmental genetic disorders associated with mutations in homeotic, segementation, zinc-finger, SOX and signal transduction genes.** (p.674, 677-680)

__Homeobox Genes__ Only two recognized human disorders are associated with HOX gene mutation: synpolydactyly and hand-foot-genital syndrome. This suggets that most HOX gene mutations are not compatible with survival.

PAX gene disorders include Waardeburg syndrome and dominantly inherited type 2 aniridia (no iris).

__Segmentation Genes__ Sonic Hedgehog (Shh) gene plays a major role in the development of the ventral neural tube and midline differentiation. Loss of function of the Shh gene gene results in holoprosencepthy (failure of midline differentiation). Errors in the Shh protein receptor //Patched// (//PTC//) gene can result in basal cell nevus syndrome (germline //PTC// mutation) or basal cell carcinoma (somatic //PTC// mutation).

__Zinc-Finger Genes__ Mutations include: //GL13// gene - Greig cephalopholysyndactyly and Pallister-Hall syndrome //WT1// gene - Wilm's tumor and Denys-Drash //ZIC3// gene - disorders of laterality.

__SOX Genes__ Loss of function of SOX9 reultsin campomelic dysplasia: underdeveloped thorax, bent limbs, sex reversal (female with XY karyotype).

__Signal Transduction Genes__ Mutations result in inability to transduce cellular signals and can lead to malignancy and developmental disorders: //ras// gene - GTP-binding; mutated in many tumors //abl// gene - cytoplasmic tyrosine kinase; CML //ret// gene - membrane tyrosine kinase; loss of function mutation leads to Hirshprung's Disease, gain of function mutation leads to medullary thyroid cancer.


 * 7. Review the mechanisms of normal male and female sexual differentiation.** (p.684, 685)

__Male Differentitaion__ SRY gene binds to DNA at a consensus sequence, possibly causing DNA bending that allows interaction of other protein products needed for sex determination. SOX-9 and DAX-1 and other autosomemal genes interact with SRY. These interactions cumulatively form embryonal testis wich secretes testosterone from Leydig cells and Steroidogeneic Factor-1 (SF-1). Testosterone stimulates the development of male differentation while SF-1 acts as a backup to regress female differentiation.

__Female Differentiation__ In the absence of the Y-chromsome, the indifferent gonand develops into an ovary. It is unclear whether or not primary ovarian differentiate requires a specific gene or occurs as the default pathway. DAX-1 has been proposed as the primary ovarian differentiation gene beacuse it appears repressed by SRY, but the subject is under debate.


 * 8. Review the common disorders of sexual differentiation with respect to their cause and phenotypic outcome.** (p.685-687)

__Pseudohermaphroditism__ SRY (+) XXmale with gonadal dysgenesis resulting from the translocation of the SRY gene to the X chromosome. X and Y chromosomes ahve a pseudoautosomal region that is used during chromosome pairing and can undergo recombination; if crossing-over occurs at the SRY region, you can get XX chromosome with the SRY gene.

__Pure Gonadal Dysgenesis__ XY female with nearly normal phenotype but cannot undergo puberty. 50% will develop gonadoblastomas. X and Y chromosomes ahve a pseudoautosomal region that is used during chromosome pairing and can undergo recombination; if crossing-over occurs at the SRY region, you can get XY chromosomes without the SRY gene.

__True Hermaphroditism__ Most commonly 46, XX with testicular and ovarian tissue. Fertility in females is rare.

__Complete Androgen Insensitivity Syndrome__ XY females with testicular tissue that secretes androgens but the androgen receptor is defective and insensitive to androgen. As a result, they develop into the female phenotype that are normal except for sparse axillary and pubic hair, short vagina, and remnants of uterus and fallopian tubes.

__Congenital Adrenal Hyderplasia__ Specific defects in enzymges of the adrenal cortex result in overproduction of androgens and virilization of female infants. Most common is a 21-Hydroxylase deficiency which causes progresterone to be unable to be converted to aldosterone or cortisol resulting in shunting towards the androgen synthesis pathway.


 * 9. Distinguish appropriate clinical indications for a prenatal cytogenetics study.** (p.691)

Indications for prenatal Cyogenetic Studies:
 * Advanced maternal age, greater than 35 years
 * Abnormal msAFP
 * Abnormal USN
 * History of two or more miscarriages
 * Known carrier parent of balanced structural rearrangement
 * Previsou child wtih chromosome abnormality
 * Sex determination for X-linked genetic disorder
 * Previous child with neural tube defect
 * Maternal anxiety


 * 10. Describe the scope and nature of chromosome abnormalities associated with pregnancy loss and infertility.** (p.690)

About 50% of genetic causes of pregnancy loss are due to undetectable cytogenetic events, molecular or immunological events, placental abnormality or other unknown causes. Over half the known causes is due to automomal trisomey with Trisomy 16 being the most common autosomal trisomy and trisomy 21 being the most common autosomal trisomy resulting in live birth. The remaining causes are due to Klinefelters, triploidy, and other causes.