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Ganglion mother cells (GMCs) are cells involved in
neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). This occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells ( ...
, in non-mammals, that divide only once to give rise to two
neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
s, or one
neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
and one
glial cell Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (the brain and the spinal cord) and in the peripheral nervous system that do not produce electrical impulses. The neuroglia make up ...
or two
glial cell Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (the brain and the spinal cord) and in the peripheral nervous system that do not produce electrical impulses. The neuroglia make up ...
s, and are present only in the central nervous system. They are also responsible for
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
expression. While each ganglion mother cell necessarily gives rise to two neurons, a
neuroblast In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as ''Drosophila,'' neuroblasts are neural progenitor cells ...
can asymmetrically divide multiple times.Doe, C. Q. et al (2008). Identification of Drosophila type II neuroblast lineages containing transit amplifying ganglion mother cells. {{PMC, 2804867. GMCs are the progeny of type I neuroblasts. Neuroblasts asymmetrically divide during
embryogenesis An embryo ( ) is the initial stage of development for a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male ...
to create GMCs.Doe, C. Q. (1992). Molecular markers for identified neuroblasts and ganglion mother cells in the Drosophila central nervous system. Development, 116(4), 855-863. GMCs are only present in certain species and only during the embryonic and larval stages of life. Recent research has shown that there is an intermediate stage between a GMC and two
neurons A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
. The GMC forms two ganglion cells which then develop into neurons or glial cells.Colonques, Jordi, Ceron, Julian, Reichert, Heinrich, & Tejedor, Francisco J. (2011). A transient expression of Prospero promotes cell cycle exit of Drosophila postembryonic neurons through the regulation of Dacapo. PLoS ONE, 6(4), e19342-e19342. Embryonic neurogenesis has been extensively studied in
Drosophila melanogaster ''Drosophila melanogaster'' is a species of fly (an insect of the Order (biology), order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly", "pomace fly" ...
embryos and larvae.


Mitotic division of Neuroblasts in Drosophila

The daughter cells of a
neuroblast In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as ''Drosophila,'' neuroblasts are neural progenitor cells ...
have two decidedly different neural fates. This is accomplished by neural fate determinants, important proteins that segregate asymmetrically. Most notable are Numb and Prospero. These proteins are evenly distributed in the
neuroblast In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as ''Drosophila,'' neuroblasts are neural progenitor cells ...
until mitosis occurs and they segregate totally into the newly formed GMC Ohshiro, T., Yagami, T., Zhang, C., & Matsuzaki, F. (2000). Role of cortical tumour-suppressor proteins in asymmetric division of Drosophila neuroblast. Nature, 408(6812), 593-596. During Mitosis Numb and Prospero localize to the basal cortex from which the GMC buds off. *Numb is a suppressor of a signal protein called Notch. Suppressing Notch signaling allows the daughter cells to react to the same signal in different ways, allowing them to have different neural fates. *Prospero is responsible for gene regulation in the GMC. Both of these proteins co-function with adapter proteins that facilitate their transition to the basal cortex during Mitosis. These proteins are Miranda and Pon. *Miranda localizes basally during interphase and then binds to Prospero, anchoring it to the basal cortex. Once the GMC has been created, Miranda releases Prospero, which evenly distributes throughout the new cell, and Miranda degrades. *Pon also known as "partner of Numb" binds to Numb and co-localizes with it during Mitosis. These four proteins act to inhibit self-renewal (the cell cycle) and promote differentiation (especially Prospero), which is why GMCs divide into their differentiated progeny instead of more GMCs. Cell cycle progression is inhibited by Prospero because it activates cyclin-dependent kinase inhibitor (CKI). The vital differentiating proteins that are segregated into the daughter
neuroblast In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as ''Drosophila,'' neuroblasts are neural progenitor cells ...
and not the GMC are Bazooka, aPKC, Inscutable, and Partner of Inscutable (Pins). The proteins (with the exception of aPKC) form a ternary complex at the apical cortex independent of the proteins that segregate towards the basal cortex. The protein aPKC promotes self-renewal, encouraging the
neuroblast In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as ''Drosophila,'' neuroblasts are neural progenitor cells ...
to keep dividing and carry out its lineage. Research has suggested that certain tumor-suppressing proteins (Lgl, Dlg, or Brat) play a critical role in the asymmetric segregation of neural fate determinants and their localization to the basal cortex . In clonal lines of
neuroblast In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as ''Drosophila,'' neuroblasts are neural progenitor cells ...
s that had been manipulated so that they lacked Lgl activity, Miranda did not segregate asymmetrically, but was evenly distributed throughout the cortex. The temporal regulation of
neuroblast In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as ''Drosophila,'' neuroblasts are neural progenitor cells ...
asymmetric division is controlled by proteins Hunchback (Hb) and sevenup (svp). After division svp accumulates in both daughter cells and down-regulates Hb. In the GMC Prospero down-regulates svp, inhibiting the temporal trigger of cellular division.Mettler, Ulrike, Vogler, Georg, & Urban, Joachim. (2006). Timing of identity: spatiotemporal regulation of hunchback in neuroblast lineages of Drosophila by Seven-up and Prospero. Development, 133(3), 429-437.


Type II Neuroblasts

Type I neuroblasts have been more thoroughly observed and researched than type II. The main difference between them is that type II gives rise do a different kind of GMC (a Transit Amplifying GMC or TA-GMC, also known as intermediate progenitors), and its lineages are generally much longer. TA-GMCs exhibits a different transcription factor from a generic GMC, Deadpan (Generic GMCs do in fact have Deadpan, but not outside of the nucleus). Type II neuroblasts do not contain detectable levels of Prospero. Unlike GMCs, TA-GMCs divide four to eight times, each time producing another TA-GMC and a generic GMC (which goes on to produce two neurons), which is why type II
neuroblast In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as ''Drosophila,'' neuroblasts are neural progenitor cells ...
s have a larger progeny than type I. Type II
neuroblast In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as ''Drosophila,'' neuroblasts are neural progenitor cells ...
s contribute a far larger population of neurons to the Drosophila brain. Recent research has shown that type II lineages are more susceptible to tumor formation than type I. When experimentally knocking out proteins such as Numb or the tumor suppressing protein Brat the entire larval brain results in tumor formation only within type II lineages. Tumor formation occurs when TA-GMCs revert to type II
neuroblast In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as ''Drosophila,'' neuroblasts are neural progenitor cells ...
s resulting in a highly increased cellular proliferation. The tumor phenotype can be suppressed with the introduction of ectopic Prospero. One of the main differences (perhaps the main difference) between type I and II
neuroblast In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as ''Drosophila,'' neuroblasts are neural progenitor cells ...
s is the presence of Prospero, suggesting that the introduction of Prospero can cause a type II
neuroblast In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as ''Drosophila,'' neuroblasts are neural progenitor cells ...
to transform into a type I identity. It is also possible that Prospero simply inhibits the proliferation of type II
neuroblast In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as ''Drosophila,'' neuroblasts are neural progenitor cells ...
s without transforming them. Type I
neuroblast In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as ''Drosophila,'' neuroblasts are neural progenitor cells ...
s that have had the gene encoding for Prospero knocked out leads to tumor formation.


Embryonic neural development in Drosophila

During the embryonic development of Drosophila,
neuroblast In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as ''Drosophila,'' neuroblasts are neural progenitor cells ...
s delaminate from their respective positions in the embryo and move towards the interior forming a ventral
monolayer A monolayer is a single, closely packed layer of entities, commonly atoms or molecules. Monolayers can also be made out of cells. ''Self-assembled monolayers'' form spontaneously on surfaces. Monolayers of layered crystals like graphene and molyb ...
of cells, known as the neurogenic region. The region is bilaterally symmetrical. The equivalent regions of neuronal growth in other common animal models do not have this symmetrical property, which makes Drosophila preferable for neurogenic study. The neurogenic region is composed of neuroblasts that divide and migrate throughout embryonic development. A larva embryo will contain about 30 neuroblasts per hemisegment of neurogenic tissue.Karcavich, Rachel, & Doe, Chris Q. (2005). Drosophila neuroblast 7-3 cell lineage: a model system for studying programmed cell death, Notch/Numb signaling, and sequential specification of ganglion mother cell identity. The Journal of Comparative Neurology, 481(3), 240-251. Karcavich, Rachel E. (2005). Generating neuronal diversity in the Drosophila central nervous system: a view from the ganglion mother cells. Developmental Dynamics: An Official Publication Of The American Association Of Anatomists, 232(3), 609-616. At a certain point, a neuroblast will undergo asymmetric cell division giving rise to a neuroblast and a ganglion mother cell. Each
neuroblast In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as ''Drosophila,'' neuroblasts are neural progenitor cells ...
can be traced through a lineage using methods such as green fluorescent protein transgene expression in order to investigate mechanisms of cellular diversity. A
neuroblast In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as ''Drosophila,'' neuroblasts are neural progenitor cells ...
lineage can produce as few as 3 GMCs or up to 20. Research has been conducted to observe the movement of neuroblasts and GMCs in the neurogenic region during embryonic development using
molecular marker In molecular biology and other fields, a molecular marker is a molecule, sampled from some source, that gives information about its source. For example, DNA is a molecular marker that gives information about the organism from which it was taken. ...
s.


Specific Neuroblast lineages of interest

In Drosophila, each
neural stem cell Neural stem cells (NSCs) are self-renewing, multipotent cells that firstly generate the radial glial progenitor cells that generate the neurons and glia of the nervous system of all animals during embryonic development. Some neural progenitor st ...
has been identified and categorized according to their location. Many
neuroblast In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as ''Drosophila,'' neuroblasts are neural progenitor cells ...
s, but not all, have also had their lineages identified (which GMCs they produce, and which subsequent neurons or
glial cells Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (the brain and the spinal cord) and in the peripheral nervous system that do not produce electrical impulses. The neuroglia make up ...
the GMCs produce). For instance the first five GMCs of NB7-1 (the neuroblast located in the 7th row and first column of the cortex) sequentially generate the U1-U5
motor neurons A motor neuron (or motoneuron), also known as efferent neuron is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly or ...
, and then subsequently 30
interneurons Interneurons (also called internuncial neurons, association neurons, connector neurons, or intermediate neurons) are neurons that are not specifically motor neurons or sensory neurons. Interneurons are the central nodes of neural circuits, ena ...
. The first GMC of NB4-2 is known to produce
motor neuron A motor neuron (or motoneuron), also known as efferent neuron is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly o ...
RP2.Grosskortenhaus, Robinson, Doe (2006). Pdm and Castor specify late-born motor neuron identity in the NB7-1 lineage. Genes and Development, 20(18): 2618–2627.


Post-embryonic neural development in Drosophila

The Drosophila CNS is composed of two brain hemispheres and the ventral ganglion. Each hemisphere is composed of a laterally located Optic lobe (OL) and a medially located, generic Cerebrum (CB). At the end of
embryonic development In developmental biology, animal embryonic development, also known as animal embryogenesis, is the developmental stage of an animal embryo. Embryonic development starts with the fertilization of an egg cell (ovum) by a sperm, sperm cell (spermat ...
neuroblast In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as ''Drosophila,'' neuroblasts are neural progenitor cells ...
s become quiescent, but re-enter their cell cycles during later specific larval stages. The most complex structures in the
insect Insects (from Latin ') are Hexapoda, hexapod invertebrates of the class (biology), class Insecta. They are the largest group within the arthropod phylum. Insects have a chitinous exoskeleton, a three-part body (Insect morphology#Head, head, ...
/Drosophila brain, the
central complex Central is an adjective usually referring to being in the center (disambiguation), center of some place or (mathematical) object. Central may also refer to: Directions and generalised locations * Central Africa, a region in the centre of Africa ...
and the
mushroom bodies The mushroom bodies or ''corpora pedunculata'' are a pair of structures in the Supraesophageal ganglion, brain of arthropods, including insects and Crustacean, crustaceans, and some annelids (notably the ragworm ''Platynereis dumerilii''). They a ...
, are responsible for
associative learning Learning is the process of acquiring new understanding, knowledge, behaviors, skills, values, attitudes, and preferences. The ability to learn is possessed by humans, non-human animals, and some machines; there is also evidence for some kin ...
and memory and do form during post-embryonic development.Boyan, George, Williams, Leslie, Legl, Andrea, & Herbert, Zsofia. (2010). Proliferative cell types in embryonic lineages of the central complex of the grasshopper Schistocerca gregaria. Cell And Tissue Research, 341(2), 259-277. Each OL is generated from three neuroepithelia called LPC (laminar precursor cells), OPC (outer proliferation center, and IPC (inner proliferation center). The OPC and IPC becomes asymmetric. Most of the development of the OL occurs at the end of the larval stage. Prospero plays a different role in post embryonic
neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). This occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells ( ...
than it did in the embryonic phase. Prospero is post-embryonically upregulated in order to promote
neurons A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
to exit the cell cycle, after GMCs differentiate during the embryogenesis Prospero is nearly undetectable.


GMCs and mammalian neurogenic research

Mammalian neurogenic research has influenced further studies. Although there is no exact equivalent of GMCs in mammalian neurogenesis, mammalian
neural stem cell Neural stem cells (NSCs) are self-renewing, multipotent cells that firstly generate the radial glial progenitor cells that generate the neurons and glia of the nervous system of all animals during embryonic development. Some neural progenitor st ...
s do produce transit amplifying progenitors that expand neural population (similar to TA-GMCs). An ortholog of Prospero in vertebrates (Prox1) is present in newly differentiating
neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
s and inhibits neural progenitor proliferation. This is similar to Prospero's effect type II
neuroblast In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as ''Drosophila,'' neuroblasts are neural progenitor cells ...
s that have expressed a tumor forming phenotype. The Prox1 protein is currently being studied as a candidate tumor suppression gene.


Transcription factor expression

A common example of a transcription factor in neuroblasts is Deadpan, which promotes neural proliferation in the Optic lobe. A previously described transcription factor in GMCs is Prospero or Pros, a transcriptional repressor. It down-regulates cell cycle gene expression to restrict GMCs to one terminal mitosis. Pros is also present in young neurons, preventing mitotic action. Prospero is not present in the progeny of GMCs and is thought to act as a timer, promoting prospective
neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
s out of their cell cycle.


Implications

Studying neurogenesis in animal models such as Drosophila comes with many advantages and leads to a better understanding of relevant human neurogenic analogs such as neural stem cells. By obtaining a better understanding of how GMCs function and the role they play in neurogenesis, it may be possible to better understand their analogs in mammals.


See also

* Virtual fly brain *
Drosophila connectome A ''Drosophila'' connectome is a list of neurons in the ''Drosophila melanogaster'' (fruit fly) nervous system, and the chemical synapses between them. The fly's central nervous system consists of the brain plus the ventral nerve cord, and both are ...


References

G Developmental neuroscience