Biochemistry Essays - Central Nervous System

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Generation of pattern and diversity in Central Nervous System

Central nervous system (CNS) is composed of brain and the spinal cord. Neurons constitute a major part of the developing CNS. An axon is an extension of a neuron. The brain grows as a swelling at the front (rostal) end of the neural tube and later leads to become a spinal cord (1,2). Development of the CNS involves many complex mechanisms beginning at the onset of transformation of a single layer of ectodermal cells, the neuroectoderm until the end of the differentiation process resulting into highly complex structure involving variety of neural cell types (1,2). A large number of cell types need to be arranged spatially and temporally to form a complex structure during an embryo development. CNS being one such complex structure formed during embryonic development involves many interlinked molecular mechanisms giving rise to interlinked and diversified neuronal circuits. Although a few of the signaling pathways (like shh) have been identified causing cellular diversity in a vertebrate CNS more studies have to be done to identify the involvements of any more of such signals. (1)

The nervous system (NS) develops from the ectoderm of a developing embryo. First to develop is the neural plate followed by formation of a neural groove in the neural plate very shortly. This is then followed by joining of the edges of the neural groove to form a neural tube, which later develops into the brain at the frontal part while the following part develops into the spinal cord. The left over cells on either side of neural tube midline form the neural crest cells, which constitute the peripheral nervous system. (1)

The vertebrate CNS originates from neural plate that in turn generates from dorsal ectoderm of gastrula- stage embryo. Neural plate closes to form the neural tube. The closure of neural tube gives rise to a chain of vesicles at the anterior –posterior axis of CNS. The most anterior portion of the neural tube gives rise to forebrain (comprising of the telencephalon and diencephalon) and the posterior portions of the neural tube form the mid- brain, hindbrain (further divided into rhombomeres) and the spinal cord. A distinct subset of cells (roof-plate) can be identified on the dorsal midline along the entire anterior- posterior axis of the CNS. Roof-plate acts as an organizing center that control mechanisms of dorsal CNS development. With the closure of dorsal end (caudal) of neural tube, arise the interneuron progenitors with non-overlapping expression of Basic helix-loop-helix (bHLH) Transcription factors (TFs) including Math1, Ngn1/2 and Mash1 in the ventricular region of the developing dorsal spinal cord. (6)

Mediators of roof-plate patterning activity in a developing spinal cord include secretory factors of BMP and Wnt signaling cascades. (6,7) It has been documented that there is a mutual antagonistic effect between Wnt and BMP signaling pathways in regulation of differentiation and proliferation of neuroepithelial cells in the dorsal spinal cord. (8). Several other signaling pathways like the retinoic acid signaling and homeodomain TF- Lbx1expression in a group of interneurons is found to be crucial for dorsal spinal cord development. However, there are evidences that had shown roof plate dependent patterning in the rostral (anterior) CNS. It is also hypothesized to influence the development of dorsal hindbrain and forebrain. (6)

The vertebrate CNS is a very complex organ that exhibits cellular diversity. The aim of developmental biology has been to solve the challenges in discovering the mechanisms that regulate or lead to the neuronal development. (2)

To decide on the interneural segment specification/ Specification of neural progenitor cells-

Drosophila has been considered as a suitable model for maximum number of studies dealing with CNS development. The CNS is made of a Ventral nerve cord (VNC) and the brain proper. Early patterning gene products help in deciding the neurogenic and non- neurogenic regions of the ectoderm. Fate mapping studies had shown that the ventral neurogenic region (VNR) forms the VNC while the procephalic neurogenic region (PNR) grows into the brain. Most of the cells at VNR form the epidermoblasts. So it is a decision by the neuroectoderm to choose between neurogenesis and epidermogenesis. Two groups of genes – proneural genes that encode transcriptional regulators of bHLH family and neurogenic genes coding for Notch signal cascade, together control the distribution of neural and epidermal progenitor cells. (2)

At the neurogenic region of the ectoderm (neuroectoderm) cells differentiate as CNS progenitor cells i.e, neuroblasts (NBs). Each of the NBs has been documented as to have aquired a unique fate determined by its position and time of formation in the neuroectoderm in each of the hemisegments. Two sets of genes (anterior – posterior and dorso –ventral) decide the positional information in each of these hemisegments. A small number of CNS progenitor cells derived from one row of mesoectoderm laying on either side between the neuroectoderm and mesoderm form the CNS midline. (2)

Out of a batch of proneural crest cells (PNCs) (undifferentiated ectodermal cells), only one may follow the cell fate to become a neural progenitor cell. Early patterning genes specify the location or site of their dwelling in the neuroectoderm and also for bHLH transcriptional activators, inturn deciding upon the competent cell out of the PNCs. The Notch signaling pathways mediates the selection of one cell to continue as neuronal progenitor cell and the rest of the cells to take the epidermal fate. There could be differences in the internal environment of the cells like different amounts of genes expressed or differences in the distribution of repressors that might affect a cell fate towards becoming a neuroprogenitor cell. (3)

Control of cell divisions in Nervous System -

The development of Nervous system (NS) depends on several external and internal factors which inturn decide the pattern of division of neurons by affecting the cell cycle behavior or cellular polarity. (3)

Neuroepithelium is a single cell layer that forms the source of developing NS in vertebrates as well as invertebrates. The progenitor cells specifically arise from these neuroepithelium and then decide to form specialized cells that differ based on their location, morphology, type of ion channels, neurotransmitter association and so on. This will determine the developmental functional aspects of the developing NS. (3). Depending on the location of the neuroepithelial cells on the neural axis and depending on the diversity of neurons at any given region of the CNS neurogenesis would differ for these cells. It is speculated that this diversity could be also due to different genetic mechanisms associated with neuronal differentiation (17). It is documented that in vertebrates, Neurogenin, a bHLH protein, a member of the proneural gene family, is expressed in the non-neurogenic ectoderm that induces neuronal differentiation.(3,17). Diversity lies behind the mechanism by which various patterning genes activate the bHLH TFs (17).

Adult Vertebrate CNS consists of 4 major cell types- neurons, oligodendrocytes, astrocytes, ependymal lining of the central lumen, all of which develop from neuroepithelial cells, which form the neural tube in an early embryo. Neuroepithelial cells are formed by induction processes and can lead to axis determination. These cells get induced by neural fate determining signals at the beginning of gastrulation and are responsible for the differentiated neural cell types forming neurons followed by glia.(17)

Symmetric and Asymmetric divisions-

It has been reported that neurons are formed by symmetric or asymmetric divisions of their progenitor cells and neural stem cells (18). During symmetric – 2 daughter cells are produced with same developmental fate, as the goal is to propagate cell population. Whereas, in asymmetric- the 2 daughter cells are produced with different cell fates such that one may be committed to a specific lineage of cells and the other will keep proliferating. There are also certain asymmetric divisions where both the daughter cells will differentiate to give rise to different lineages, trying to reach different locations. Both the kinds of divisions are regulated by a group of proteins involved in cell cycle like the cyclins, cyclin-dependent kinases and its inhibitors (3). It was found that cell divisions during NS development is regulated at every stage from the beginning when progenitor cells are specified for following a particular path, till they exit the cell cycle and differentiate. (3,18). Symmetric/ asymmetric divisions of neuroepithelial and radial glial cells were decided based on the inheritance of either both or only one of the daughter cells. Tis21 is a molecular marker (antiproliferative gene), that was reported to be expressed only in dividing neuroepithelial cells at the beginning of neurogenesis and not on proliferative neuroepithelial cells (18,23). It has also been documented that vertical cleavage (plane radially aligned in ventricular zone) result in symmetric and proliferative divisions of the neuroepithelial and radial glial cells such that both the daughter cells such that both the daughter cells get equally distributed amounts of apical and basal constituents. On the horizontal cleavage (cleavage plane parallel to the apical surface) of the ventricular zone give rise to asymmetric cell divisions because one of the daughter cells will get the apical constituents while the other gets the basal. However it has been also reported that Vertical cleavages could also give rise to asymmetric division of neuroepithelial cells (18).

The epithelial characteristics (like the apical-basal polarity and cell cycle length) of these cells decide the division type, differentiation pattern and proliferation of these cells. Also certain features undergo a change while transforming from neuroepithelial to radial glial cells, which also is believed to affect neuronal pattern generation and diversity. (18).

Pattern of cell division in neural progenitor cells-

The entire developmental process of neurogenesis includes steps of transition into neurogenic progenitor (NP) cells, exiting the cell cycle after division of atleast one daughter cell and its differentiation into a neuron or glial cell (23).Each cell of NB or neural progenitor cell divides to give rise to one daughter NB and another daughter, which is the ganglion mother cell (GMC), committed to form a pair of post mitotic neurons. While the larger size NBs are associated with apical region of neuroepithelium, the smaller size GMCs migrate basally into the embryo. Also gene expression of asense and deadpan are found in NB while it gets repressed in the GMCs whereas genes like even-skipped and fushi tarazu, which are expressed in GMC are repressed in NB. Hence one or combination of the neuronal precursor genes could be involved in controlling the asymmetric cell division of NBs (3). Delta-Notch expression regulates some of the mechanisms during differentiation process. It was reported that Tis21 expression begins only after NP expressing delta1 divide (23). Hence delta- notch is involved in regulation between transition from proliferation to neurogenesis in NP cells. Also markers like HES proteins were found to be essential in maintaining undifferentiated state of NP cells (23).It is speculated that delta1 function to maintain selected NP cells in predifferentiated state until differentiation gradients were encounterd by them. (23).

Precursors of neurons, neuroglia and ependymal cells in the CNS-

CNS comprises of 3 distinct neural cell types- neurons, neuroglia (astrocytes + oligodendrocytes) and ependymal cells. The precursor of all these 3 types are present as undifferentiated cells in the epithelium of the neural plate and its successor, neural tube at the primary stage (5). Neuroepithelium composed of the neuroepithelial cells form a single layer of the lining of the neural tube and neural plate before neurogenesis begins (18). It is documented that a proper composition of adherent functions (like protein AF6) is essential for the apical-basal polarity of neuroepithelial cells(18). Gradually with enlargement of the cerebral vesicles and thickening of the neural wall, these primitive neuroepithelial cells elongate retaining a radial orientation till they travel. Neural precursors or cells manage to cross over the ventricular wall and migrate to different regions of the CNS via translocation. This has been found in neocortex region due to translocation of neuroblasts (that differentiated from these precursors). (5)

Glial influences on Neural SC development-

New neurons are constantly generated in distinct and highly specialized regions of the mammalian CNS that are uniquely regulated during development process (4). Unlike neuro epithelial cells radial glial cells result in the formation of only one cell type – either astrocyte, oligodendrocyte or majority of the time into neurons. It was reported that chances of differentiation are found to be more with neuroepithelial cells and so the glial cells comprise of the differentiated progeny of neuroepithelial cells. This shows a change in fate restriction during transition from one cell type to another (18). It has been reported that a type of glia cells- the astrocytes are involved in deciding the specificity of neuronal progenitor cells while regulating their proliferation, migration or integration with an already established neuronal signaling cascade, within these microenvironments. This was found pronounced in the hippocampal compared to the spinal cord. It is under study to understand the cascade of signaling pathways in these micro- environments that might be responsible for the mechanisms involved in neurogenesis in various parts of the brain. (4). It has been documented that microglia can effect the near by neurons carrying a tag/receptor mechanism on its surface, which on a damaged neuron gets activated by Caspase-3 expression and result in either neuronal death or axonal proliferation in mammalian CNS (19). Its been observed that microglial cells on encountering signals of pathological attack from neurons enter into either an undifferentiated state and stop its proinflammatory activity or induce the neurons with chemokines, purines and glutamate for benfecial/ not so beneficial effects depending on the surrounding environment. (20)

The newly formed neurons have the tendency to migrate and join with the pre-existing neuronal circuits in adult CNS and contribute to brain function. The surrounding microenvironments need to support SC activation, self- renewal and differentiation in response to other factors. In vitro as well as invivo several mitogens like the shh, fibroblast growth factor (FGF) and epidermal GF ligands have been found to propagate the adult neural SCs by Notch and mitogen signaling and astrocytes are known to express. Also astroglia derived Wnt signaling was found to promote neurogenesis of adult Neural Stem Cells (NSCs) while bone morphogenetic protein (BMP) family signaling makes NSCs to take up a glial cell fate and not neuronal. Noggin is one such molecule –antagonistic to BMP. (4)

Specification of dorsal spinal cord neurons-

Based on the genes that are expressed will depend the expression of the molecular markers, pattern of projections, kind of neurotransmitters on the dorsal spinal cord interneurons. The genes expressed help these factors to choose the fate of development of the neural tube and also decide its dorsal-ventral polarity. (7)

It is also reported to have aided in establishing the function of heilx- loop-helix and homeodomain TFs in neuronal cell-type specification. Studies have identified roof-plate as an essential signaling center for dorsal interneuron specification. Many bone morphogenetic protein (BMP) gradients are expressed on roof plate and epidermal ectoderm, which can induce dorsal neuronal cell types and hence function in deciding cell fate specification. Gradients of BMP signals have been found to be involved in development of neural crest cells and a group of dorsal sensory neurons in the spinal cord. Constitutive expression of BMP signaling receptors also influence bHLH expression in progenitor cells and in specification of interneuron types in dorsal neural tube. TFs –Pax3 and Pax7 are thought to be included by BMP signals and are expressed at dorsal part of neural tube in response to repression from sonic hedgehog (shh). (7)

Radial Glia serves as Neuronal progenitors (NP) -

Using Cre/Lox P fate mapping studies and clonal analysis it has been reported that majority of the neurons in the CNS originate from radial glia cells and so they serve as NP. The pattern of brain lipid binding protein (BLBP) and astrocyte specific glutamate transporter (GLAST) induced in almost all neocortical radial glia give rise to a neurogenic gradient. BLBP is found to be high in ventral portions compared to dorsal at earlier stages ehich indicate that regional differences influence the timing of radial glial neurogenesis. (9)

Axon development and regeneration-

During nerve generation peripheral neurons get induced with epidermal/ epithelial Fatty acid- binding protein ( E- FABP) while the central neurons accumulate E-FABP at higher concentrations during migration and development of neurons. It has been reported that E-FABP expression allows normal outgrowth of neurons in PC12 cells with Nerve growth factor (NGF). Allen and et al group had studied its effect on retinal ganglion cell (RGCs) differentiation and axon growth in rats at embryonic- postnatal - adult stage. It was found that E-FABP is expressed in RGCs when it formed the ganglion cell layer as well as was important during axonal develoment and regeneration. (10)

Specific Control of Neuronal migration –

Neurons undergo a difference in their rate of migration while moving through different cortical layers. Pituitary Adenylate cyclase- activating polypeptide (PACAP) has been reported to influence the migration of early postnatal neurons by slowing them in cerebella and external granular layer (EGL) but not in the Purkinje cell layer (PCL) or internal granular layer (IGL). However, PACAP antagonist does affect the migration pattern incase of molecular layer, external granular layer or internal granular layer. It did increase migration in Purkinje cell layer. Also signaling cascades involving cAMP and the activity of phospholipase C were found to decrease the effect of PACAP on cell migration. PACAPs effect is found to be effective for only two hours following which it gets desensitized. PACAP is reported to be sporadically present in PCL and over IGL. It thus acts as a signal for migrating neurons to tell them when to stop migrating once they reach the layers rich in PACAP. Thus cerebellar cortical layer containing granular cells are regulated by endogeneous PACAP. (11)

Some more mechanisms involved in neuronal migration and morphogenesis in CNS-

Preselinin1 (Psen1) is important for axial skeleton development as well as neuronal differentiation. Its function is documented as to be associated with various transmembrane proteins like the Notch, which is important during embryogenesis and also found to be involved in processing of intra membrane b- amyloid precursor protein. It was documented that Psen1 K/O mutants had shown impaired axis development and neuronal differentiation due to defective radial and tangential migration of interneurons from different regions into a specific part of the nervous system. These migrations were also associated with different signals, cell-adhesion molecules and or regulatory proteins that had guided in axonal development. (12)

A conserved homeodomain in Homeobox (Hox ) genes regulate embryonic morphogenesis and hence play a role of transcriptional regulator in vertebrates and Drosophila in which they were first discovered (22).Booth and et al had studied the expression pattern of the downstream target genes of the Hox genes during neuronal development (21). The Hox protein regulatory activity depends on the interaction between different transcriptional factors in a transcriptional complex and this behaviuor is consistent in a developing CNS along the anterior-posterior and dorsal-ventral axis of the embryo. (22) Myelin oligodendrocyte glycoprotein (MOG) was found to be one of the downstream target of Hoxd1 genes. Specific sequences (TAAT sequences) adjacent to these target gene (TAATTG core) was found to be essential for binding to the MOG promoters by the Hox (21). Further investigations are needed to understand which are those target genes that are being regulated by these Hox genes and what mechanisms do they contribute in development of the CNS. It is speculated that these target genes could be responsible for various signaling molecules or cell adhesion molecules which might contribute to differentiation and later neuronal diversification and specification during early CNS development. (22)

The signaling mechanism that might be responsible for a halt in migration of immature neurons in CNS development was proposed to involve loss of transient rise of Ca²+. Increasing cAMP or internal reservoirs of Ca²+ had shown to delay granule cell migration. Inhibiting the activity of phospholipase C, PKC or Ca²+/ Calmoduline also had shown to slow down granule cell migration. Ca²+ signaling is found to influence other signaling cascades that aid in mediating migration of immature neurons. (13)

One of the regulatory TFs that play an important role in the development of the CNS is the bHLH protiens (24,25). The family includes HES, OLIG, NPAS and NEUROD (24). Studies suggest that the CNS developmental process by multiple HLH genes is regulated via a feed back loop. A group of HLH genes cause the differentiation of precursors and another group of non- neuronal HLH genes would inhibit the same differentiation. This will help to maintain a balance between the number of neurons generated and their distribution pattern in the brain (25). It was documented that on an average there were 22 target genes for each of these TFs, however more than one TF can regulate the same target gene. The binding preferences of other TFs on the promoter of the genes on DNA remain speculative and needs further research (24)

Spindle pole arrangement-

Semaphorins (membrane protein) have been reported to induce rearrangement of the actin and microtubule skeleton and also guide axonal projections and reorganize synaptic complexes. Its production is correlated with axonal growth in a developing embryonic brain. (14). Neuroepithelial cleavage plane has been found to depend on the position of the poles of the mitotic spindle. (18)

Like Semaphorins (for e.g, Sema3A) PlexinC1 are found to act as axonal attractants or repellants that would influence GABAergic neuron migration. (15,16). Plexins have been found to respons to Semaphorins (16). It has been documented that Plexin C1 (receptor) are expressed during migration of neurons in the developmental process whileSema7A (ligand) are found to be elevated during the later developmental stages (adult stage) when PlexinC1 expression diminishes. Sema7A was found to promote axon growth invitor. The 2 receptors that were found to function in response to Sema7A were: RGD- dependent a1b1-integrin and Plexin C1 from Plexin family but this is still speculative. It is known that b1-integrins and Sema7A are involved in axon growth and immune functions. Using a PlexinA3 K/O mice model it was found that Plexin A3 was essential in regulation of axonal projection in hippocampus via Sema3F and Sema 3A signal (16). However, the relation between Plexin C1 and Sema7A for neuronal growth is under research. (15)

Conclusion -

Although few of the neuronal cell differentiation mechanisms have been described here many are yet to be explored. Understanding the mechanisms of neuronal diversification shall shed light on the mechanisms that might be responsible for behavioral patterns , different causes of brain diseases and so on and inturn might provide guiding cues to therapy dealing with nerve disorders. A combined and detailed study using molecular, genetic, biochemical and embryological or developmental analysis will help us to identify the mechanisms that lie behind the signaling pathways, or gene regulation by TFs; during induction and patterning of a neuronal lineage in CNS development.

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