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Asymmetric Cell Division in the Drosophila Neuroblast

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					           Asymmetric Cell Division in the
              Drosophila Neuroblast


Asymmetric cell division is the process by which certain cells divide, producing

unevenness between the two daughter cells. This unevenness can take the form of a

difference in size, a difference in the distribution of cellular components, or a

combination of both. Examples of this type of division are seen throughout nature.

Budding yeast divide asymmetrically by the creation of daughter buds that pinch off the

mother and are noticeably smaller. It can be seen in plant cells, whereby a mother

epithelial cell divides asymmetrically to reproduce itself and a smaller guard mother cell

which in turn gives rise to two guard cells lining the stomata of the leaves. The

nematode C. elegans uses the process of asymmetric cell division as a basis for

mapping out its body plan in the very first division of the embryo. However, the most

interesting model organism where asymmetric cell division has been studied is in

Drosophila melanogaster. In the Drosophila embryo, there are a number of symmetrical

divisions which give rise to an epithelial layer. Within this epithelium, some cells are

given cues to assume a neural fate and delaminate from the epithelial layer. These

cells are the progenitor cells of the neurons which will eventually become the nervous

system of the larval Drosophila. These neuroblast cells then divide asymmetrically to
produce another neuroblast cell as well as a much smaller ganglionic mother cell

(GMC). Finally, the GMC then divides asymmetrically to produce two neurons with

different allocations of cellular components, but of similar size.


The pathway involved in the process of division from neuroblast mother cell to

neuroblast and GMC daughters to neurons is a complex process involving many

different protein pathways. Not only are the two daughter cells of different size, but the

proteins contained within them are drastically different as well. The discovery and

understanding of how these pathways work to produce this asymmetric division has

been a long process and its entirety still continues to elude the scientific community.

Starting from the discovery of what are called fate determinants, to understanding the

process of spindle orientation, to the recent realization that cell cycle regulators play an

additional role in affecting asymmetric cell division, the veil cast over a beautiful and

intricate mechanism has been lifted and only now are we beginning to see how

everything fits together.




To begin this journey of understanding how the asymmetric division of the neuroblast is

achieved, first there must be a general overview of what happens in this process. As

stated before, some epithelial cells in the drosophila embryo are given cues governed
by gene signalling to assume a neuronal fate (White and Kankel 1978). These cells

then lose their adherens junctions and delaminate from the epithelium and are then

called neuroblasts. Neuroblasts then undergo a process by which certain proteins,

called fate determinants, are segregated to opposite sides of the cell. While this is

occurring the spindle, which is responsible for separating the duplicated chromosomes,

rotates 90 degrees (Kaltschmidt et al. 2000). This rotation causes the cell to divide in

along the plane which separates the apical region from the basal region. This is

perpendicular to the epithelial cells from which it delaminated, that divide in a

posterior/anterior manner. The spindle midbody then moves basally where the

cleavage furrow is forming, resulting in a daughter cell which retains its neuroblast

identity and a smaller daughter cell which takes of the identity of a ganglionic mother

cell (Bingwei et al. 1998). This identity change of the GMC is due to certain proteins

which were preferentially allocated to the GMC daughter during the division of the

neuroblast mother cell. These fate determinants govern the process by which the GMC

loses its self-renewing properties and divides only once more to produce two neurons

(Doe et al 1991).




The first fate determinant was called Numb, which was originally discovered in sensory

organ precursor (SOP) cells, and was shown there to confer different fates to the
daughter cells of the SOP (Rhyu et. al 1994). Numb is a signalling protein containing an

N-terminal phosphotyrosine binding domain which has been found to interact with a

signal transduction pathway known as the Notch pathway. Specifically numb acts as a

linking protein between an α-adaptin protein and the Notch protein which facilitates the

endocytosis and repression of Notch (Knoblich et al 1997). This pathway in the GMC is

thought to be responsible for the determination of the position of the axon in the

developing neuron cells. It has been seen that since the Numb protein maintains its

position in the apical cortex of the GMC, it becomes preferentially segregated to one of

the neuron daughter cells. This means that only one neuron will have a repression of

the Notch pathway, and that repression is thought to direct the axon growth on the

posterior side of the cell. Opposite this, the other cell will have a fully functioning Notch

pathway and the axon growth will occur on the anterior side (Bingwei et al. 1998).


The second fate determinant is named Prospero. This protein is a transcription factor,

and after segregation to the basal cortex of the neuroblast mother cell, and subsequent

transfer into the GMC, it enters the nucleus of the GMC and is responsible for activating

and repressing certain genes which specify the fate of the GMC (Doe et al. 1991).

Prospero contains a homeodomain and binds to the DNA upstream of approximately

700 genes and is known to repress genes that are involved in maintaining self renewal

capabilities as well as upregulate genes involved in halting the cell cycle and directing
division into the two neuron daughter cells. This homeodomain consists of two regions,

a highly divergent homeodomain adjacent to a conserved novel Prospero domain. The

Prospero domain region is involved directly with the binding to DNA (Ryter et al. 2002).

Interestingly, not only is Prospero preferentially segregated into the GMC, but an RNA

transcript of Prospero is segregated as well. This transcript is brought to the GMC from

the neuroblast by a protein named Staufen (Ferrandon et al. 1994). Staufen is a double

stranded RNA binding protein that was discovered in the Drosophila oocyte, where it

plays a role in the localization of RNA transcripts to both the anterior and posterior poles

of the oocyte (Li et al. 1997). The double-stranded binding domain found in Staufen is a

fairly common one consisting of approximate 65 amino acids and is conserved from

bacteria to humans. Staufen contains 5 copies of this motif and it has been shown that

the 3rd copy binds to double-stranded RNA in vitro (Bycroft et al. 1995). In the

neuroblast, Staufen binds ProsperoRNA and localizes it to the basal cortex. After

division Staufen is known to release ProsperoRNA into the cytoplasm of the GMC. The

apparent reason for this transfer of an RNA transcript into the GMC is because the

GMC is not known to transcribe Prospero itself. This is in addition to the fact that the

Prospero mRNA transcript is a very long transcription unit that takes approximately 20

minutes to transcribe from the DNA. The current view is that the mRNA transcript was
delivered to the GMC at cell division in order to avoid delays in the next cell division by

having to wait until more Prospero RNA was transcribed (Li et al. 1997).


The third and latest fate determinant to be discovered goes by the name of Brain

Tumour (Brat). Brat is a member of a family of tumour suppressor proteins that has

been evolutionarily conserved (Betschinger et al. 2006). This protein consists of a 1037

amino acid chain containing two Bbox zinc finger domains, a coiled coil domain and a

C-terminal beta-propeller domain, all of which are known to mediate protein-protein

interactions (Slack and Ruvkun 1998). Although currently the exact mechanism by

which Brat operates is unknown, the fact that it plays a role in tumour suppression

(Betschinger et al. 2006) suggests that Brat works in conjunction with Prospero to inhibit

cell growth, cause the loss of self-renewal function in the GMC, and induce the GMC to

undergo terminal differentiation resulting in two neurons.




These fate determinant proteins do not localize themselves to the basal cortex and

segregate into the GMC at cell division. There are two proteins that act as scaffolds to

bind and move the determinants to the basal pole of the neuroblast and ensure they

end up in the GMC. The first of these proteins to be discovered was Miranda, and

consequently much is known about this protein. Miranda is an adaptor protein that
contains a coiled coil region known to bind the proteins Prospero, Staufen, and Brat

(Shen et al. 1997, Ikeshima-Kataoka et al. 1997, Lee et al. 2006). In the neuroblast cell,

Miranda initially is localized at the apical cortex then moves to the basal cortex where it

tethers its cargo to the cortex and awaits cell division (Matsuzaki et al. 1998). Once

division occurs, Miranda then dissociates and releases its protein cargo into the

cytoplasm (Schuldt et al. 1998). Miranda first accumulates in the cytoplasm during

interphase, then it is recruited to the apical cortex by a protein named Inscuteable,

which will be discussed later, where it forms an apical crescent (Kraut et al. 1996). At

this point a number of things occur which causes Miranda to be excluded from the

apical cortex and redistributed into the cytoplasm. First, atypical Protein Kinase C

(aPKC) phsophorylates a protein named Lethal (2) giant larvae (Lgl) (Lee et. al 2006).

This phosphorylation causes the inactivation of Lgl, which in turn allows for the

activation of Myosin II. Myosin II is responsible for the exclusion of Miranda from the

apical cortex (Erben et al. 2008). Once Miranda is localized in the cytoplasm, another

protein, Myosin VI, interacts with Miranda and helps transport it to the basal cortex. It is

not known whether Myosin VI then acts as an anchor to tether Miranda to the cortex or

if there is another anchor protein involved (Erben et al. 2008). After cell division,

Miranda is now tethered to the apical region of the GMC. It has been discovered that

the Miranda protein contains a number of consensus sequences that allow it to be
targeted for destruction (Fuerstenburg et al. 1998). These destruction boxes show

similarity to the destruction boxes that exist in the cell regulators cyclins A and B. The

theory is that Miranda is degraded by ubiquitination, causing the release of Staufen,

Prospero and Brat into the cytoplasm of the GMC (Schuldt et al. 1998).


The fate determinant Numb is localized and tethered to the cortex by a different adaptor

protein by the name of PON (Partner of Numb). PON is also a coiled-coil protein which

binds only Numb, and although it helps in localizing Numb to the basal cortex, it has

been shown that it is not strictly required for the localization (Lu et al. 1998).

Experiments have uncovered that the mechanisms responsible for the asymmetrical

localization acts on Numb as well as PON (Wang et al. 2007), although recently it was

discovered that Myosin II plays a major role in localizing PON, and therefore Numb to

the basal cortex (Erben et al. 2008). It should be noted that after cell division, PON

doesn’t release Numb from the cell cortex. Numb remains there and it is there it acts to

repress the Notch pathway. This tethering to the cell cortex of the GMC is also

responsible for its preferential segregation into only one of the neuron daughter cells (Lu

et al. 1998).
In the neuroblast it is of grave importance that polarity between the apical and basal

sides of the cell be set up and maintained. The proteins responsible for this were

originally discovered in C. Elegans, and their homologues were then found in

Drosophila (Knoblich 2008). These proteins are named Bazooka, Par-6 and aPKC,

mentioned earlier. Bazooka is a large protein containing three PDZ domains, required

for anchoring proteins to the cytoskeleton of the cell (Schober et al. 1999). Bazooka

protein is found in the apical cortex of all epithelial cells in the drosophila embryo, where

it helps maintain apical/basal polarity. Because epithelial cells divide laterally, Bazooka

is distributed equally between the two epithelial daughter cells. This apical localization

of Bazooka is maintained when some cells assume a neuronal fate and delaminate to

become neuroblasts. In the neuroblast, Bazooka is responsible for recruiting the protein

Inscuteable, which has ties to other protein localization as well as spindle orientation

and will be described later (Wodarz et al. 1999). Par-6 is a smaller protein containing

only one PDZ domain and shares a similar role as Bazooka, although it is not

responsible for recruiting Inscuteable. Par-6 does however interact with the cell cycle

regulator cdc42, which is responsible for its apical localization to the cell cortex (Atwood

et al. 2007). Par-6 also interacts with aPKC causing it to be localized to the apical

cortex as well. These three proteins are the main players in providing localization

information for the processes involved in asymmetric cell division.
Although it has be said that how cell fate determinants are localized asymmetrically

remains the greatest mystery of asymmetric cell division, recent studies have begun to

uncover the mechanisms that lay behind this (Kaltschmidt et al. 2000). Previously it has

been shown how Myosin II and VI interact with Miranda and Numb to transport the

proteins to the basal cortex of the neuroblast, although this seems only to be the tip of

the iceberg. The protein Lgl, as well as aPKC has been shown to play a part in this

localization process by interacting with each other in a negative way (Lee et al. 2006).

Because Lgl is normally found throughout the cytoplasm and is directly inactivated by

aPKC which phosphorylates three serines on Lgl thereby preventing it from binding to

the actin cytoskeleton (Betschinger et al. 2005), Lgl is only found in an active form at the

basal cortex. This dance between Lgl activation/inactivation by aPKC was thought to be

directly involved in the asymmetric localization of fate determinants until it was found the

Lgl does not bind to any of these proteins (Lee et al. 2006). The current theory is that

Lgl and aPKC indirectly localize fate determinants by interacting with the cortical binding

sites of the determinants with aPKC inhibiting the sites, or Lgl activating them (Chia et

al. 2008).
The final process necessary for a neuroblast to undergo asymmetric cell division is the

coordination of the orientation of the spindle with the asymmetric localization of the fate

determinants during mitosis. In neuroblast cells, as previously stated, the spindle

rotates 90 degrees, and the midbody moves toward the basal cortex of the cell so that

when division occurs, not only does the cell divide perpendicular to the epithelial cells,

but the division results in a neuroblast daughter cell that is 75% larger than the GMC

daughter cell on average (Morgan 2007). The main protein responsible for the correct

orientation of the spindle is named Inscuteable. Inscuteable is a novel protein, 859

amino acids in length containing a 252 amino acid domain named the asymmetry

domain and is partly responsible for directing the orientation of the spindle (Kraut et al.

1996, Schober et al. 1999). Inscuteable is recruited to the apical cortex by Bazooka

through an interaction in a 100 amino acid coiled coil domain, where it forms a complex

with a number of other proteins, namely Pins (Partner of Inscuteable), Discs large (Dlg),

Mushroom body defect (Mud), Canoe, and a heterotrimeric G protein subunit, Gαi

(Schaefer et al. 2000, Cai et al. 2003, Speicher et al. 2008). Inscuteable recruits Pins to

the apical cortex where it binds the protein. Pins then binds Gαi by way of three GoLoco

domains that exist of the C-terminal domain of Pins (Nipper et al. 2007). This binding

not only tethers Pins to the cortical membrane, but also causes Pins to undergo a

conformational change and allows it to bind the protein Mud. Mud is a microtubule
binding protein that is thought to act as a dock for astral microtubules, which makes it

partly responsible for the orientation of the spindle poles (Siller et al. 2006). Recently it

was found that the protein Canoe, which is known to be a scaffolding protein containing

kinesin-like and myosin V-like domains, also forms in a complex with Inscuteable-Pins-

Gαi, and that it acts upstream of Mud, helping with the orientation of the spindle

(Speicher et al. 2008).


Although the precise mechanisms for the orientation of the spindle are unclear, it is

known that the mechanisms are dependent on where the centrosome is located in the

cell (Kaltschmidt et al. 2000). Before replication, the location of the centrosome dictates

the direction of the orientation of the spindle. If the duplication occurs in the apical

region of the cell, the posterior centrosome moves basally in a counter-clockwise

manner. However, if the duplication occurs in the basal region, the anterior centrosome

moves apically in a clockwise fashion (Kaltschmidt et al. 2000).


This method of spindle orientation and movement is unique to the drosophila

neuroblast. Normally in asymmetric cell division, the spindle poles are formed and one

pole basically maintains its position, moving slightly back and forth, whereas the other

pole moves away from the middle of the cell towards the outer cortex (Morgan 2007).

This causes the midbody to move from the center of the cell and the creation of a

cleavage furrow is formed at the location of the midbody leading to an asymmetrical
division. This type of division can be seen in the C. Elegans embryo and results in one

daughter cell being two thirds larger than the other. In drosophila, it is interesting to see

how the spindle is reoriented and how the astral microtubules, which attach to the

chromosomes, undergo differences in growth and reduction. The apical microtubules

lengthen dramatically, while the basal ones shorten. This results in the movement of

the spindle midbody towards the basal region of the cell (Morgan 2007). In most cases

of cellular division, it has been shown that the spindle midbody dictates the position of

the cleavage furrow and subsequent cytokinesis (Cai et al. 2003). In the neuroblast

however, a very unique event occurs. As the midbody moves towards the basal region

of the cell, the cleavage furrow has already started to invaginate (Kaltschmidt et al.

2000). This discovery has only been seen in the case of the neuroblast and goes

contrary to the popular belief that the midbody dictates the site of cleavage.




Apart from the unique proteins that facilitate asymmetric division, the direction a lot of

research has turned to recently is the involvement of cell cycle regulators and kinases

and their role in this process. It is known that the kinase Aurora A functions in the

process of centrosome maturation and spindle formation when activated by TPX2

(Morgan 2007), however it was discovered that Aurora A has an inhibitory function on

the cell’s ability to self renew (Berdnik and Knoblich 2002). This was conjoined with the
discovery that Aurora A also functions in the localization of Numb to the basal cell

cortex, although the mechanism by which it does this is not certain (Barros et al. 2005).

Another cell cycle regulator, Polo, has also been shown to play a role in the localization

of Numb. The experiments that determined these separate functions of the cell cycle

regulators were brought about by monitoring cells with phenotypes that involve a

mutation in the Aurora A, and Polo transcribing genes (Wang et al. 2007). As the

neuroblast cell attempted to divide asymmetrically, it was seen that Numb was either

distributed throughout the cytoplasm, or that a crescent of the protein was formed, just

not at the basal cortex where it normally would be found.


The G1 cell cycle regulator CyclinE was found to play a key role in the determination of

neuroblast cell fate this year. Previously it had been discovered that Prospero

represses the expression of CyclinE (Choksi et al. 2006), but this discovery brought to

light that CyclinE also inhibits the function of Prospero. This negative feedback loop

has been deemed essential in the decision of the neuroblast to continue to divide, or

enter into differentiation into the GMC, and subsequent neuronal cells. CyclinE was

found to inhibit Prospero function by affecting its localization to the cell cortex by

potentially phosphorylating the protein and causing a disruption in its ability to bind to

Miranda (Berger et al. 2010). This function of CyclinE was also found to be

independent of its role in cell cycle regulation.
The act of asymmetrical cell division has turned out to be a very complex and intricate

cascade of proteins that interact with each other in order to facilitate the neuroblast cell

cycle. Starting from the delamination of the neuroblast from the cortical epithelia of the

neuroectoderm, the protein Bazooka interacts with aPKC and recruits the protein

Inscuteable and PAR6 to form a complex that not only acts in directing the localization

of the cell fate determinants Miranda and PON and maintaining the overall polarity of

the cell, but also interacts with the complex formed by Pins, Gαi, Dlg, Canoe, and Mud

in directing the proper spindle orientation and facilitate the lengthening/shortening of the

astral microtubules of the spindle. Miranda acts in the localization of the cell fate

determinants Prospero and Brat by acting as a transporter protein to tether the fate

determinants to the basal cortex of the cell. Miranda also binds Staufen, which in turn

binds the Prospero mRNA transcript as well. Numb is localized to the basal cell cortex

by the transport protein PON, which along with Miranda utilize the proteins Myosin II

and VI to transport their respective protein cargo to the cortex for segregation into the

GMC daughter cell. In addition to this, it has recently been discovered that the regular

cell cycle kinases Polo and Aurora A assist in the localization of Numb to the basal

cortex in addition to their regular known function. As well, the cell cycle regulator,

CyclinE is suggested to inhibit the function of Prospero which allows for the neuroblast
cell to maintain its self-renewal capabilities. These discoveries have opened the door

for new work on stem cell research (Knoblich 2008), and in conjunction with that, cancer

research. This stems from the realization that some stem cells do divide

asymmetrically, and that the regulation between symmetric and asymmetric division is

essential to tumourigenesis (Caussinus and Gonzolez 2005). As the pathways that

facilitate asymmetric division become clear, it is undeniable that we are coming one

step closer to understanding the mysteries of the development of life itself.
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