How Flies Have Helped the Understanding of Nervous System Development



Model organisms, such as the fruit fly Drosophila, are instrumental in understanding the fundamental mechanisms that underpin biological processes. For example, Drosophila has helped extensively to clarify the mechanisms underlying nervous system development (neurogenesis), most of which turned out to be conserved in higher animals. This article will briefly summarise what aspects of neurogenesis have benefited from Drosophila research and then focuses on asymmetric neural cell division to explain how such research is carried out in the fly.


Aspects of Neurogenesis


The vast majority of neurons in animals are produced at the early stage of embryonic development in a process called neurogenesis. Neurogenesis can be roughly subdivided into a number of steps, and to the understanding of most of these, Drosophila has contributed significantly. These steps (Figure 1) include:


A. Specification of neural progenitor cells (Figure 1A); defining and patterning of the neurogenic area and selecting neural precursors through the process of lateral inhibition. Neurogenic cells located in ectoderm, through the process of lateral inhibition, give rise to neuroblast and sensory organ precursor cells. 


B. Generating pools of neurons (Figure 1B); asymmetric cell division. Neuroblasts segregate from ectoderm and divide asymmetrically to give rise to either another neuroblast or a ganglion mother cell. Asymmetric cell division depends on the asymmetric distribution of the proteins that mediate this process.


C. Neural differentiation (Figure 1C); axon and dendrite growth as well as synapse formation. Ganglion mother cells divide once and give rise to postmitotic neurons, which form many neural cell types such as interneurons and motoneurons. These cells form axons by projecting out growth cones and establishing contact with their target cells.


D. Glial differentiation (Figure 1D); neural migration and morphogenesis of their shape. Unlike neuroblast precursor cells, sensory organ precursors remain in the epidermis. They divide twice and give rise to sheath cells and one sensory neuron.



Most of the fundamental mechanisms of nervous system development that were discovered in Drosophila later turned out to be conserved in mammals including humans. Therefore using Drosophila has been instrumental in understanding brain formation. In addition, work on Drosophila continues to be instrumental in unraveling the genetic and molecular basis of these fundamental mechanisms. Hence Drosophila represents a valuable ‘test tube’ for brain-related research.


Asymmetric Cell Division


The fruit fly, Drosophila, has played an instrumental role in discovering and understanding asymmetric cell division. The term asymmetric cell division refers to one stem cell dividing into two daughter cells; however, one daughter cell takes a different identity than the other, which usually remains stem cell like (Figure 2). Asymmetric cell division has a fundamental importance in stem cell biology since this process gives rise to many tissues, through mechanisms that seem widely conserved.


How Drosophila Was Used During the Discovery and Research on Asymmetric Cell Division


In mid-nineties, scientists noticed that a protein called Numb asymmetrically associates to half of sensory organ precursor (SOP) cells, which eventually form the peripheral nervous system of Drosophila. During SOP division Numb was segregated to ganglion mother cells, which form neural cells. Loss of Numb caused SOP cells to produce no neurons and its ectopic expression caused the formation of excess neurons. Therefore Numb determines the identity (fate) of the secondary precursor cells and its asymmetric distribution generates an asymmetric cell division in which daughter cells acquire distinct fates.


It is now known that asymmetric distribution of proteins such as Numb allows other structures such as spindle fibers to attach to them, which leads to asymmetric cell division through a pinching process (Figure 2). Numb is amongst plethora of proteins such as Pins, Insc, Baz, DaPKC and PAR-6, which are involved in asymmetric cell division. The genes encoding the above proteins were originally identified in Drosophila due to their effects on embryonic patterning and neural precursor (also know as neuroblasts) polarity. Loss-of-function mutations in these genes leads to similar phenotypes in neuroblasts, including randomised orientation of spindle fibers.


With recent development of green fluorescent protein (GFP) tagged molecules, it has become possible to track the various events during the asymmetric cell division of neuroblasts. Vertebrate homologues of Numb and Notch molecules, know to be involved in determining cell fate in Drosophila, have been observed to localise asymmetrically in dividing neural progenitor cells.




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