Quintessential Questions In Developmental Neurobiology Biology Essay

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One of the quintessential questions in developmental neurobiology is how an undifferentiated neuroepithelium in the embryo can produce unparalleled cellular diversity and specialization in the mature nervous system. One of the most important, yet underestimated types of cells present in the embryonic neural system is the glial cells. Glial cells, which make up an approximate of 90% of the brain (Andrew Koob - The Root of Thought), are cells present in the central nervous system (CNS) and the peripheral nervous system (PNS), providing support to the brain's neurons and also maintaining homeostasis. Of most primary use, the oligodendrocytes and most Schwann cells produce myelin sheaths (The Human Nervous System- Structure and Function, Noback and Strominger).

This essay will look into the differentiation of two types of glial cells; Schwann cells (PNS) and oligodendrocytes (CNS). Glial specification in structure and function is of utmost importance in the ever increasing neural complexity. The Schwann cells (SC) and oligodendrocytes are cells which arise from completely different lineages. (REFERENCE REQUIRED). The former develop from the neural crest cells originating from the dorsal tips of the neural tube (Jessen, Mirsky, 2009). Conversely, the oligodendrocytes, develop from the sub-ventricular regions of the lateral ventricles of the neural tube (The Human Nervous System- Structure and Function, Noback and Strominger). However, both these cell types require a common family of molecules for their efficient development, proliferation and functioning, namely, laminin.

Laminins are glycoprotein molecules which are predominantly found in basal lamina. (*). Comprising of one of the key members of the extracellular matrix (ECM), laminins consist of trimeric molecules containing binding sites for varied receptors, predominantly integrins. (Colognato et al, 2005). This essay concentrates on the process with which laminins regulate cell behaviour of two different types of glial cells, arising from completely distinct cell lineages. It tries to put forward the basic concept that several such molecules may exist in the vertebrate system which may be important for the understanding and hence emergence of future strategies to bring about repair. The papers on which this review is based, Yu et al, 2009 and Colognato et al, 2009, explicitly show that Schwann cell differentiation and proliferation, and development of oligodendrocytes from their progenitors, are both affected by the deficiency of laminin, respectively.

Origin of SCs and oligodendrocytes:

The neural crest cells give rise to SCs precursors which further differentiate into promyelinating or non-myelinating cells. The SCs which are programmed to myelinate, have the essential function of proliferating and extending cytoplasmic processes into axon bundles. Thus, they establish a one-to-one ratio with the large axons (Mirsky and Jessen, 1999). (axonal sorting) There is a large amount of literature corroborating the concept that SCs require the formation of a basal lamina to myelinate (Bunge, 1993). SCs lacking laminin have been recorded to have impaired axon interaction, which in turn leads to their stunted proliferation and differentiation (Yu et al, 2005).

(ORIGIN OF OLIGOS - neuroglia book ) In order to form oligodendrocytes which are capable of producing myelin, the OPC has to first differentiate into a post-mitotic oligodendrocyte which then undergoes morphological changes to produce myelin. These changes are brought into effect by existing cell cycles which are in turn regulated by laminin (Buttery et al, 1999).

As is evident from above, laminin is prevalent in two very discrete processes, and hence is a family of intriguing molecules which may have a potential of bringing about simultaneous repair in the CNS and PNS, in the case of glial cell disorders.

Schwann Cells and Laminin

The axonal sorting performed by SCs is achieved by several steps, namely proliferation, spindle shape formation and process extension. In the paper of Yu et al (2009), it was exhibited that laminin is required for SC bipolar morphology and process extension. Moreover, SCs lacking laminins do not myelinate. Feltri et al (2002) have also reported that SCs devoid of β 1 integrin, a laminin receptor, show incomplete axonal sorting. SCs that lack the laminin subunit usually result into the loss of laminin expression due to which there is severe reduction in proliferation (Yu et al, 2009).

Rac 1 and Cdc-42 are important GTPase members which also play pivotal roles in axonal sorting. Rac 1 acts downstream of β 1 integrin activation (Benninger et al, 2007). Moreover, SCs are detected using anti-S100 anitbody while myelin is detected using anti-MBP antibody. The first point Yu et al (2009) raised was whether laminins regulate the bipolar morphology of SCs. In order to do this, they used time-lapse live-cell imaging on mouse SC-dorsal root ganglion (DRG) co-cultures with the addition on ascorbate to stimulate basal lamina deposition. They reported that after 8 days, most SCs in the control coculture had a bipolar morphology and also segment of myelin. On the other hand, laminin devoid of SCs did not myelinate and also did not form a bipolar shape. (DOES PROCEDURE OF EXPTS HAVE TO BE WRITTEN?) Yu et al (2009) also showed that SCs which lacked laminins were not able to innervate axon bundles. This suggested that laminins regulate extension during sorting. The SCs were identified using anti S-100 antibody. The myelin was detected using anti-MBP antibody. The cells were then viewed via confocal microscopy. By means of this procedure, it was clearly observed that the mutant SCs showed a lesser degree of process extension as compared to the control.

A major breakthrough in this paper was the finding of the regulation of both Rac 1 and Cdc-42 by laminins. Rac 1 brings about process extension (Nodari et al, 2007) while activated Cdc-42 is required for cell proliferation. Previously it was reported that Cdc- 42 was activated by NRG-1 (Grove et al, 2007), which in turn phosphorylated the ErbB receptors. However, this was investigated further by Yu et al (2009), by performing immunoblot assays of the lysates of the co-cultures for phospho-ErbB2. Surprisingly, it was found that the level of phosphor-ErbB2 was decreased by a big margin in the co-cultures which lacked laminins. Thus, this exhibited the fact that laminins regulate both the Cdc42 and Rac 1 pathways. This suggests that laminins regulate the proliferation as well as process extension of SCs. Other findings by the same authors also report the depletion of all laminins once the laminin γ1 gene is disrupted in the PNS (Yu et al, 2005). This investigation also showed that SCs lacking laminins cannot accomplish the downregulation of Oct-6 transcription factor (which is required for the transition of SCs from premyelinating stages to myelinating SCs - Bermingham et al, 1996). Moreover, by studying the sciatic nerves of mutant mice (with disrupted laminin γ1 gene), they reported that SCs-axon interactions which are mediated by laminins are crucial for Schwann cell proliferation. They put forward a hypothesis stating that axons are a massive source of SCs mitogens. Hence, an impaired axon-SC relationship gave rise to reduced SC proliferation.




Oligodendrocytes and Laminin

Myelination, the primary function of oligodendrocytes, is an example of intricate cellular specialization. Oligodendrocytes produce large amounts of myelin which wrap around mature axons and facilitate saltatory conduction (Buttery et al, 1999). In order to develop into myelin-producing cells, oligodendrocytes undergo two distinct steps. The first consists of the differentiation of oligodendrocyte progenitor cells (OPCs) into post-mitotic oligodendrocytes which express markers for differentiation (like, MBP). The second step consists of a drastic change in the morphology of the oligodendrocytes which is associated with the production of myelin membrane (Buttery et al, 1999). It is this membrane which consists of molecules of laminin.

Colognato et al in 2009 carried out an extensive study on the effect of laminin on oligodendrocyte development involving the Fyn rmechanisms. In this paper, they reported that in laminin-deficient mice, the development of oligodendrocytes was delayed. They also found that there was severe accumulation of OPCs in the adult brains.

One of the important signalling molecules in oligodendrocyte development is the Fyn molecule (an Src-family kinase). This regulates the process formation and degree of myelination in oligodendrocytes (Colognato et al, 2005). In their 2009 paper, they put forward a theory suggesting that the process of oligodendrocyte differentiation is guided by laminin-mediated signalling. By carrying out experiments on mutant mice (dy/dy) with mutations in the LAMA2 gene (for ECM production of laminin-α2), they successfully proved the link between laminin and Fyn and hence oligodendrogenesis (Colognato et al, 2009). Chun et al in 2003 reported that the corpus callosum and optic nerve were hypomyelinated in the case of dy/dy mutant mice. To evaluate this further, Colognato et al studied both, OPCs as well as oligodendrocytes in dy/dy brains. Their results show that there is significant reduction in the number of mature oligodendrocytes in the mutants when compared with the wild type (wt)littermates. They also investigated in other regions of the brain and found similar results. On evaluating levels of MBP in the cerebral cortices, they reported that less MBP was observed in the mutants as opposed to the wt.

In order to determine if there is delayed differentiation of OPCs in dy/dy brains, Colognato et al examined the number of PDGFRα(+) (OPC +) cells in various regions of the brain. They reported a significant increase in PDGFRα(+) cells in the dy/dy mutants than in the wt, proving that there is a delay in differentiation of oligodendrocytes in laminin devoid systems. The most interesting and unique investigation that they undertook was to check if laminin promoted OPC differentiation. By placing the cells in contact with laminin-2 substrates, they studied whether the loss of laminin caused reduced Fyn phosphorylation in OPCs.



Interestingly, from the above summary of experiments, it is apparent that the work presented by Yu et al, 2009 and Colognato et al, 2009 presents strong evidence of the dependency of development of both SCs and oligodendrocytes on laminin. The deficiency of laminin in peripheral nerves leads to paralysis and motor dysfunction (Strickland et al, 2003). Laminin also

There is major difficulty to detect the presence of laminins in the CNS as basal lamina rich in ECM molecules are rare. Due to this, a massive amount of research has not been put into the effect of laminins on oligodendrocyte development (Colognato et al, 2005). However, abnormalities like MDC are present due to an inaccuracy in the development of SCs and oligodendrocytes in the PNS and CNS respectively. Further research into laminins and their effect on the development and proliferation of these cells could probably help us understand the mechanisms of synthesis and repair failures in greater depth, thus facilitating the evaluation of the role of laminin in the nervous system.