Ganglion mother cell

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Type I neuroblast gives rise to a GMC and an identical neuroblast, as opposed to type II whose daughter cells are known as intermediate neural progenitors (INPs). The GMC then differentiates into two neurons. Neuroblast cell division - 486169.fig.002a.jpg
Type I neuroblast gives rise to a GMC and an identical neuroblast, as opposed to type II whose daughter cells are known as intermediate neural progenitors (INPs). The GMC then differentiates into two neurons.

Ganglion mother cells (GMCs) are cells involved in neurogenesis, in non-mammals, that divide only once to give rise to two neurons, or one neuron and one glial cell or two glial cells, [2] and are present only in the central nervous system. They are also responsible for transcription factor expression. While each ganglion mother cell necessarily gives rise to two neurons, a neuroblast can asymmetrically divide multiple times. [3] GMCs are the progeny of type I neuroblasts. Neuroblasts asymmetrically divide during embryogenesis to create GMCs. [4] 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. The GMC forms two ganglion cells which then develop into neurons or glial cells. [5] Embryonic neurogenesis has been extensively studied in Drosophila melanogaster embryos and larvae.

Contents

the signal protein Notch is exposed to both daughter cells of a neuroblast (another neuroblast and a GMC). Because Numb (represented by the blue line) is a Notch suppressor and only present in the GMC, the GMC will behave differently from the other daughter cell, the neuroblast. Asymmetric cell division neuroblast.jpg
the signal protein Notch is exposed to both daughter cells of a neuroblast (another neuroblast and a GMC). Because Numb (represented by the blue line) is a Notch suppressor and only present in the GMC, the GMC will behave differently from the other daughter cell, the neuroblast.

Mitotic division of Neuroblasts in Drosophila

The daughter cells of a neuroblast 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 until mitosis occurs and they segregate totally into the newly formed GMC [6] During Mitosis Numb and Prospero localize to the basal cortex from which the GMC buds off.

Segregation of transcription factors during asymmetric division of a type I neuroblast Asymmetric cell division in Drosophila neuroblasts - 486169.fig.004.jpg
Segregation of transcription factors during asymmetric division of a type I neuroblast

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.

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. [3] Cell cycle progression is inhibited by Prospero because it activates cyclin-dependent kinase inhibitor (CKI). [5]

The vital differentiating proteins that are segregated into the daughter neuroblast 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 to keep dividing and carry out its lineage. [3] [6]

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 . [6] In clonal lines of neuroblasts 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 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. [7]

Type II Neuroblasts

An example of a brain tumor occurring as a result of GMCs reverting to the neuroblast stage. Most likely caused by the absence of the Numb or Brat proteins in a type II neuroblast or possibly and absence of Prospero in a type I neuroblast Abnormal neuroblast proliferation and brain tumor formation - 486169.fig.005a.jpg
An example of a brain tumor occurring as a result of GMCs reverting to the neuroblast stage. Most likely caused by the absence of the Numb or Brat proteins in a type II neuroblast or possibly and absence of Prospero in a type I neuroblast

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. [3] 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 neuroblasts have a larger progeny than type I. Type II neuroblasts contribute a far larger population of neurons to the Drosophila brain. [1] 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. [1] Tumor formation occurs when TA-GMCs revert to type II neuroblasts 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 neuroblasts is the presence of Prospero, suggesting that the introduction of Prospero can cause a type II neuroblast to transform into a type I identity. [1] It is also possible that Prospero simply inhibits the proliferation of type II neuroblasts without transforming them. Type I neuroblasts that have had the gene encoding for Prospero knocked out leads to tumor formation. [1]

Embryonic neural development in Drosophila

During the embryonic development of Drosophila, neuroblasts delaminate from their respective positions in the embryo and move towards the interior forming a ventral monolayer of cells, known as the neurogenic region. [4] 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. [2] At a certain point, a neuroblast will undergo asymmetric cell division giving rise to a neuroblast and a ganglion mother cell. Each neuroblast 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 lineage can produce as few as 3 GMCs or up to 20. [2] Research has been conducted to observe the movement of neuroblasts and GMCs in the neurogenic region during embryonic development using molecular markers. [4]

Specific Neuroblast lineages of interest

In Drosophila, each neural stem cell has been identified and categorized according to their location. Many neuroblasts, but not all, have also had their lineages identified (which GMCs they produce, and which subsequent neurons or glial cells 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, and then subsequently 30 interneurons. The first GMC of NB4-2 is known to produce motor neuron RP2. [8]

Post-embryonic neural development in Drosophila

representation of neurogenesis in optic lobe development. During larval development the neuroepithelial cells(orange) transform into neuroblasts. NE cells undergo symmetric proliferation with a horizontal spindle orientation to expand the pool of precursor cells and give rise to asymmetrically dividing neuroblasts(green). Median neuroblasts divide asymmetrically with a vertical spindle orientation, localizing proteins i.e. Prospero. Neurogenesis in optic lobe development - 486169.fig.003.jpg
representation of neurogenesis in optic lobe development. During larval development the neuroepithelial cells(orange) transform into neuroblasts. NE cells undergo symmetric proliferation with a horizontal spindle orientation to expand the pool of precursor cells and give rise to asymmetrically dividing neuroblasts(green). Median neuroblasts divide asymmetrically with a vertical spindle orientation, localizing proteins i.e. Prospero.

The Drosophila CNS is composed of two brain hemispheres and the ventral ganglion. [5] Each hemisphere is composed of a laterally located Optic lobe (OL) and a medially located, generic Cerebrum (CB). At the end of embryonic development neuroblasts become quiescent, but re-enter their cell cycles during later specific larval stages. [5] The most complex structures in the insect/Drosophila brain, the central complex and the mushroom bodies, are responsible for associative learning and memory and do form during post-embryonic development. [10] 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. [5] Prospero plays a different role in post embryonic neurogenesis than it did in the embryonic phase. Prospero is post-embryonically upregulated in order to promote neurons to exit the cell cycle, after GMCs differentiate during the embryogenesis Prospero is nearly undetectable. [5]

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 cells do produce transit amplifying progenitors that expand neural population (similar to TA-GMCs). [3] An ortholog of Prospero in vertebrates (Prox1) is present in newly differentiating neurons and inhibits neural progenitor proliferation. This is similar to Prospero's effect type II neuroblasts that have expressed a tumor forming phenotype. The Prox1 protein is currently being studied as a candidate tumor suppression gene. [1]

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. [3] Prospero is not present in the progeny of GMCs and is thought to act as a timer, promoting prospective neurons out of their cell cycle. [5]

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

Related Research Articles

The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The field of neural development draws on both neuroscience and developmental biology to describe and provide insight into the cellular and molecular mechanisms by which complex nervous systems develop, from nematodes and fruit flies to mammals.

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 which divide asymmetrically to produce a neuroblast, and a daughter cell of varying potency depending on the type of neuroblast. Vertebrate neuroblasts differentiate from radial glial cells and are committed to becoming neurons. Neural stem cells, which only divide symmetrically to produce more neural stem cells, transition gradually into radial glial cells. Radial glial cells, also called radial glial progenitor cells, divide asymmetrically to produce a neuroblast and another radial glial cell that will re-enter the cell cycle.

<span class="mw-page-title-main">Rostral migratory stream</span> One path neural stem cells take to reach the olfactory bulb


The rostral migratory stream (RMS) is a specialized migratory route found in the brain of some animals along which neuronal precursors that originated in the subventricular zone (SVZ) of the brain migrate to reach the main olfactory bulb (OB). The importance of the RMS lies in its ability to refine and even change an animal's sensitivity to smells, which explains its importance and larger size in the rodent brain as compared to the human brain, as our olfactory sense is not as developed. This pathway has been studied in the rodent, rabbit, and both the squirrel monkey and rhesus monkey. When the neurons reach the OB they differentiate into GABAergic interneurons as they are integrated into either the granule cell layer or periglomerular layer.

Neuroepithelial cells, or neuroectodermal cells, form the wall of the closed neural tube in early embryonic development. The neuroepithelial cells span the thickness of the tube's wall, connecting with the pial surface and with the ventricular or lumenal surface. They are joined at the lumen of the tube by junctional complexes, where they form a pseudostratified layer of epithelium called neuroepithelium.

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 stem cells persist in highly restricted regions in the adult vertebrate brain and continue to produce neurons throughout life. Differences in the size of the central nervous system are among the most important distinctions between the species and thus mutations in the genes that regulate the size of the neural stem cell compartment are among the most important drivers of vertebrate evolution.

The subependymal zone (SEZ) is a cell layer below the ependyma in the lateral ventricles of the brain. It is an adult version of the embryonic forebrain germinal zone. This region contains adult neural stem cells, also called neuroepithelial cells, which have the potential to generate new neurons and glial cells. The generation of neurons and glial cells from neuroepithelial cells occurs via neurogenesis and gliogenesis, respectively. In adults, the subependymal zone is also called the subventricular zone, as the ependymal cell layer forms the boundary between the fluid-filled ventricular space and the walls of the lateral ventricles.

<span class="mw-page-title-main">Radial glial cell</span> Bipolar-shaped progenitor cells of all neurons in the cerebral cortex and some glia

Radial glial cells, or radial glial progenitor cells (RGPs), are bipolar-shaped progenitor cells that are responsible for producing all of the neurons in the cerebral cortex. RGPs also produce certain lineages of glia, including astrocytes and oligodendrocytes. Their cell bodies (somata) reside in the embryonic ventricular zone, which lies next to the developing ventricular system.

<span class="mw-page-title-main">Subventricular zone</span> Region outside each lateral ventricle of the brain

The subventricular zone (SVZ) is a region situated on the outside wall of each lateral ventricle of the vertebrate brain. It is present in both the embryonic and adult brain. In embryonic life, the SVZ refers to a secondary proliferative zone containing neural progenitor cells, which divide to produce neurons in the process of neurogenesis. The primary neural stem cells of the brain and spinal cord, termed radial glial cells, instead reside in the ventricular zone (VZ).

An asymmetric cell division produces two daughter cells with different cellular fates. This is in contrast to symmetric cell divisions which give rise to daughter cells of equivalent fates. Notably, stem cells divide asymmetrically to give rise to two distinct daughter cells: one copy of the original stem cell as well as a second daughter programmed to differentiate into a non-stem cell fate.

<span class="mw-page-title-main">Subgranular zone</span>

The subgranular zone (SGZ) is a brain region in the hippocampus where adult neurogenesis occurs. The other major site of adult neurogenesis is the subventricular zone (SVZ) in the brain.

<span class="mw-page-title-main">NUMB (gene)</span> Protein-coding gene in the species Homo sapiens

Protein numb homolog is a protein that in humans is encoded by the NUMB gene. The protein encoded by this gene plays a role in the determination of cell fates during development. The encoded protein, whose degradation is induced in a proteasome-dependent manner by MDM2, is a membrane-bound protein that has been shown to associate with EPS15, LNX1, and NOTCH1. Four transcript variants encoding different isoforms have been found for this gene.

Neurogenins are a family of bHLH transcription factors involved in specifying neuronal differentiation. It is one of many gene families related to the atonal gene in Drosophila. Other positive regulators of neuronal differentiation also expressed during early neural development include NeuroD and ASCL1.

Gliogenesis is the generation of non-neuronal glia populations derived from multipotent neural stem cells.

Endogenous regeneration in the brain is the ability of cells to engage in the repair and regeneration process. While the brain has a limited capacity for regeneration, endogenous neural stem cells, as well as numerous pro-regenerative molecules, can participate in replacing and repairing damaged or diseased neurons and glial cells. Another benefit that can be achieved by using endogenous regeneration could be avoiding an immune response from the host.

Corticogenesis is the process during which the cerebral cortex of the brain is formed as part of the development of the nervous system of mammals including its development in humans. The cortex is the outer layer of the brain and is composed of up to six layers. Neurons formed in the ventricular zone migrate to their final locations in one of the six layers of the cortex. The process occurs from embryonic day 10 to 17 in mice and between gestational weeks seven to 18 in humans.

Proneural genes encode transcription factors of the basic helix-loop-helix (bHLH) class which are responsible for the development of neuroectodermal progenitor cells. Proneural genes have multiple functions in neural development. They integrate positional information and contribute to the specification of progenitor-cell identity. From the same ectodermal cell types, neural or epidermal cells can develop based on interactions between proneural and neurogenic genes. Neurogenic genes are so called because loss of function mutants show an increase number of developed neural precursors. On the other hand, proneural genes mutants fail to develop neural precursor cells.

<span class="mw-page-title-main">Neuronal lineage marker</span> Endogenous tag expressed in different cells along neurogenesis and differentiated cells

A neuronal lineage marker is an endogenous tag that is expressed in different cells along neurogenesis and differentiated cells such as neurons. It allows detection and identification of cells by using different techniques. A neuronal lineage marker can be either DNA, mRNA or RNA expressed in a cell of interest. It can also be a protein tag, as a partial protein, a protein or an epitope that discriminates between different cell types or different states of a common cell. An ideal marker is specific to a given cell type in normal conditions and/or during injury. Cell markers are very valuable tools for examining the function of cells in normal conditions as well as during disease. The discovery of various proteins specific to certain cells led to the production of cell-type-specific antibodies that have been used to identify cells.

<span class="mw-page-title-main">Ventricular zone</span> Transient embryonic layer of tissue containing neural stem cells

In vertebrates, the ventricular zone (VZ) is a transient embryonic layer of tissue containing neural stem cells, principally radial glial cells, of the central nervous system (CNS). The VZ is so named because it lines the ventricular system, which contains cerebrospinal fluid (CSF). The embryonic ventricular system contains growth factors and other nutrients needed for the proper function of neural stem cells. Neurogenesis, or the generation of neurons, occurs in the VZ during embryonic and fetal development as a function of the Notch pathway, and the newborn neurons must migrate substantial distances to their final destination in the developing brain or spinal cord where they will establish neural circuits. A secondary proliferative zone, the subventricular zone (SVZ), lies adjacent to the VZ. In the embryonic cerebral cortex, the SVZ contains intermediate neuronal progenitors that continue to divide into post-mitotic neurons. Through the process of neurogenesis, the parent neural stem cell pool is depleted and the VZ disappears. The balance between the rates of stem cell proliferation and neurogenesis changes during development, and species from mouse to human show large differences in the number of cell cycles, cell cycle length, and other parameters, which is thought to give rise to the large diversity in brain size and structure.

Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs), radial glial cells (RGCs), basal progenitors (BPs), intermediate neuronal precursors (INPs), subventricular zone astrocytes, and subgranular zone radial astrocytes, among others.

Intermediate progenitor cells (IPCs) are a type of progenitor cell in the developing cerebral cortex. They are multipolar cells produced by radial glial cells who have undergone asymmetric division. IPCs can produce neuron cells via neurogenesis and are responsible for ensuring the proper quantity of cortical neurons are produced. In mammals, neural stem cells are the primary progenitors during embryogenesis whereas intermediate progenitor cells are the secondary progenitors.

References

  1. 1 2 3 4 5 6 Bayraktar, Boone, Drummond, Doe (2010). Drosophila type II neuroblast lineages keep Prospero levels low to generate large clones that contribute to the adult brain central complex. Neural Development, 5:26.
  2. 1 2 3 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.
  3. 1 2 3 4 5 6 Doe, C. Q. et al (2008). Identification of Drosophila type II neuroblast lineages containing transit amplifying ganglion mother cells. PMC   2804867.
  4. 1 2 3 Doe, C. Q. (1992). Molecular markers for identified neuroblasts and ganglion mother cells in the Drosophila central nervous system. Development, 116(4), 855-863.
  5. 1 2 3 4 5 6 7 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.
  6. 1 2 3 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ Nidhi Saini and Heinrich Reichert, “Neural Stem Cells in Drosophila: Molecular Genetic Mechanisms Underlying Normal Neural Proliferation and Abnormal Brain Tumor Formation,” Stem Cells International, vol. 2012, Article ID 486169, 10 pages, 2012.
  10. ↑ 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.
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