The molecule that controls neurogenesis

The brain is perhaps one of the most complex machines that evolution has ever created and without a doubt, the most efficient and versatile computer in existence today. The human brain can perform a mind boggling one thousand trillion logical operations per second, and it consumes a paltry 20 watts of energy in the process. To do this, the brain uses close to 100 billion neurons, or nerve cells, arranged in a complex architecture that scientists are still deciphering. The nervous system as a whole extends beyond the brain, as a network of electrical connections that innervate the entire body, constantly transmitting information to and from the decision making centres in the brain.


Signalling pathway

But how, where and when does this complex network of neurons start to develop? The quest for finding answers to these questions makes neurogenesis one of the most fascinating areas of study in neuroscience. While some aspects of neurogenesis are known, the field is still nebulous, with many unanswered questions regarding how an embryo, developing from a single cell, can build an intricate and complex network of different kinds of nervous tissues that we see in a fully developed brain. In fact, the biological processes behind neuronal development are hot areas of research today. Now, scientists at the Indian Institute of Science Education and Research (IISER), Pune, have discovered a key mechanism that regulates the development of neurons and sensory organs in the common fruit fly (Drosophila melanogaster).  

Previous studies on neurogenesis have shown that the ‘Notch signalling pathway’, present in most multicellular organisms, is responsible for the growth of the nervous system in an embryo. ‘Notch’, the central player involved in the development of the nervous system, is a receptor protein that sits on the cell membrane. When activated by a specific signal, this receptor prevents cells around it from receiving or responding to the same signal, in a process called ‘lateral inhibition’.

The mechanism of preventing these signals gives rise to the ‘specification’ of a unique cell — a process where generic cells of the embryo start developing into specific cells constituting a tissue or an organ system. In neurogenesis, this process of specification turns the progenitors of neurons, into well-developed neurons, surrounded by many identical cells. Through lateral inhibition, a single layer of embryonic cells can develop into manifold structures that look and function poles apart from their precursors.

In a recent research article published in the March 2017 issue of the journal Development, Professor L S Shashidhara and his team, have uncovered a key regulator of ‘Notch’, a protein that is involved in neurogenesis, through a process called lateral inhibition. The researchers believe that figuring out how Notch is regulated is a big step towards understanding the formation of nervous tissue. “Lateral inhibition is ‘the’ mechanism of generating neurons, which means the brain itself. During development, when a single-cell embryo divides and organises itself, the ectoderm, because of Notch function, divides into epidermis (skin) and the nervous system,” says Shashidhara.

Shashidhara’s team used fruit flies as model organisms of their study and have discovered a molecule that controls Notch, and thereby effectively orchestrates the formation of the hair like sensory bristles that cover the entire body of the fly. The molecule, called drosophila Ataxin-2 binding protein-1 or dA2BP1, also has a human counterpart which is implicated in complex neuronal disorders such as spinocerebellar ataxia.


Essential role

Using a variety of genetic, cell biology and biochemical techniques, the researchers have shown that the protein dA2BP1 directly binds to the Notch protein present on the cell surface, and is essential for Notch to carry out its functions. By performing various experiments, they have observed that removal of dA2BP1 increased the number of sensory bristles on the fruit fly, and increasing the levels of dA2BP1 resulted in a severe loss of bristles as well as the bristle forming precursor cells.

The implications of this study are far reaching. Apart from providing scientists with an improved view of the neurogenesis process, the discovery of dA2BP1 as a Notch regulator brings us one concrete step further to understanding and hopefully reversing genetic neurodegenerative disorders like Huntington’s disease and spinocerebellar ataxia. “As the function of Notch signalling is similar across organisms – from Drosophila to humans,
and Notch is implicated in many diseases, its functional understanding also helps in understanding diseases,” signs off Shashidhara.


The author is with Gubbi Labs, a Bengaluru-based research collective