Advanced Molecular Genetics-Biology 566 Molecular Mechanisms of Germline Stem Cell Regulation
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Germline Stem Cells

"A unique undifferentiated cell that has the ability to self-renew and generate differentiated cell types ." (Wong, Jin, and Xie, 2005)

GSCs

"Germline stem cells that have the ability to regenerate itself."

IGSs

"Inner germarial sheath cells that support differentiation ."

Niche

"The molecular nilieu or microenvironment formed by support cells that express regulatory molecules that promote stem cell self-renewal and block differentiation." (Wong, Jin, and Xie, 2005)

Assymetric cell division

"cell division generating two daughter cells that have different cell fates ." (Wong, Jin, and Xie, 2005)

Intrisic factors

"factors that act within the cell to control its behavior ." (Wong, Jin, and Xie, 2005)

Extrinsic Factors

"factors that function outside the cell for controlling its behavior ." (Wong, Jin, and Xie, 2005)

Fig. 1. Structure and development of Drosophila ovarian follicles. (A) A drawing of a Drosophila ovariole, showing the anterior germarium (ger) followed by a string of eight successively older ovarian follicles connected by interfollicular stalks. The position of the polar cells is shown (red). Each egg chamber stage is indicated above (see Spradling, 1993). As a result of egg elongation during stages 8-14, mature stage 14 egg chambers are 20-fold longer than stage 2 egg chambers in the AP axis, but only seven times wider in the DV axis. Somatic cells are shown in green, whereas nurse cells and the oocyte are tan; the germline stem cells and forming cysts are illustrated in red and orange, respectively. (B) A magnified view of the germarium showing regions 1, 2a, 2b and 3. Cell types are indicated by the same colors as in A, except that the intercyst cells at the end of region 2b (arrow) are in dark blue, while the non-dividing somatic cells that surround region 1 and 2a are shown in light blue. (C) A magnified view of the follicular epithelium from a stage 8 follicle. The apical and basal orientation of the follicle cells can be seen with respect to the basement membrane (red) and the nurse cells. (http://dev.biologists.org/cgi/content-nw/full/128/16/3209/FIG1)

How did they define functions?

By using heat-inducible FLP, which is a flippase, a DNA recombinase, combined with a FRT, which is a FLP recognition target, target mediated recombination can produce marked mutant GSC clones that can be compared with the control GSC clone side-by-sitde in the same germarium.

Extrinsic Factors

BMP and Piwi are produced from cap cells.

BMPs such as Dpp and Gbb signal through type 1 receptors such as Tkv and Sax and type II receptors such as Put to nuclear complexes Mad and Med.

-Mutations lead to loss of GSC by premature differentiation.

-Overexpression completely blocks cystoblast differentiation resulting in GSC-like tumors.

Piwi and Yb are expressed in niche cells and are involved in GSC maintenance. Piwi contains conserved domains that bind to RNAs. Hh signaling appears to play a redundant role with Piwi to control GSC maintenance.

-Mutations lead to rapid loss of GSC.

-Overexpression leads to cystoblast-like germ cells.

Stet mutants in IGS cells inhibit cystoblast differentiation. Stet is a membrane protease that can cleave and release EGF ligands, supporting the activations of MAP kinase in IGS cells.

Intrinsic Factors

Pumilio (Pum) and Nanos (Nos) are RNA binding proteins that form protein compleses that repress translation of mRNAs.

-Mutations lead to rapid loss of GSC.

Vasa (Vas) encodes a homologue of eIF4A.

-Mutations lead to few growth-arrested germ cells.

Conclusion: Translation regulation plays a critical role in GSC self-renewal.

E-cadherin and Armadillo expressed in cap cells and form adherens junctions which anchor GSC to cap cells.

Cyclin B required for promoting divisions and helps control GSC maintenance either by cell-cycle regulation or direct interaction with the GSC maintenance machinery.

Bam and Bgch are RNA binding proteins that are essential to differentiation. These proteins may form complexes that regulate mRNA stability or translation.

-Mutations abolish cystoblast differentiation, leading to a systoblast-like germ cell tumor.

-Overexpression leads to triggers GSC differentiation and germ cell depletion in ovary.

Orb and Sxl proteins are involved in regulation of mRNA polyadenylation and translation respectively .

-Mutations accumulation of GSC-like or cystoblast-like cells.

Zero population growth (Zpg) is present in cytoplasmic membranes and is required to maintain GSC and to promote germ cell differention. May function in parallel with bam.

-Mutations results in partial GSC loss due to cell death.