Uncovering the Second Brain

Here’s a brief introduction to a part of the nervous system you’ve probably never thought about.  Alisha Linton, a 2nd year NGP student, writes about the Enteric Nervous System.

Did you know that there are more neurons in your gut than in the brain of a cat? Cats have approximately 300 million neurons in their brain, while your gut contains almost 500 million neurons9. If this is new information, you are not alone. Most people don’t know that your gastrointestinal (GI) system is controlled by its own population of neurons, functioning with little to no input from the central nervous system (aka brain and spinal cord, CNS). These neurons are located in the wall of the gut and control a variety of functions such as motility, mucus secretion and blood flow within the gut. Collectively, this is called the Enteric Nervous system (ENS), and it is often call the “second brain”. The intrinsic innervation of the gut was first identified in the early 1900s by Bayliss and Starling1,2, and was deemed separate from the peripheral nervous system (PNS) and the CNS. The ENS communicates using signaling molecules (neurotransmitters and neuromodulators) such as acetylcholine, serotonin and nitric oxide, just like the other parts of the nervous system. In fact, 95% of the body’s serotonin is made in the gut while only 2% of all serotonin is made in the brain.Slide1

The gastrointestinal tract is a layered tube that contains an epithelial layer, two muscle layers and two neuronal layers. Going from the inside of the gut working outward, the first layer is the mucosal layer which absorbs nutrients from food passing through the lumen and secretes mucus to protect the epithelial cells lining the lumen. Right underneath the mucosa is the submucosa, which contains glands and blood vessels. Beneath this is the first nervous component of the gut, the submucosal plexus. This plexus controls gland secretion and bloodflow. Next, we reach the muscular component of the gut which is made up of two layers, a circular and longitudinal muscle layer. Sandwiched between these two layers is the myenteric plexus, which controls function of both muscle layers, and thus overall motility of the gut. The two neuronal layers: the submucosal plexus and the myenteric plexus make up the ENS. Within these plexuses neuronal cell bodies are grouped together into structures called ganglia. These ganglia are scattered along the entire length of the gut. Axons project out of one ganglion to other adjacent ganglia, allowing for information to travel up and down the GI tract. Within these ganglia there are many different neuronal subtypes, including excitatory and inhibitory motor neurons, interneurons, and supporting cells, or glia.

As one might imagine, the development of the ENS and the PNS are a bit different than the development of the CNS. While the CNS is formed from the neural tube, neurons outside of the central nervous system are formed from something called the neural crest. These are cells that are fated to become neurons, but not contained within the neural tube proper. During development, neural crest cells migrate from right beside the neural tube to their final destination within the walls of organs, such as the heart, gallbladder, liver and GI tract.Slide2

The enteric nervous system in particular is formed by neural crest cells derived from the vagal (near the head) and the sacral (near the tail) regions of the spinal cord3,4,5,11. The migration of these neural crest cells is some of the longest of all migrating neural crest cells, taking about 3 weeks in human gestation6. To form the nervous component of the gut, these neural crest cells travel from the vagal region, down through the developing gut tissue, and extend downward to populate the entire length of the gut. This process requires many migration and proliferation cues which occur via a variety of genes and transcription factors, including glial derived neurotropic factor (GDNF) and Ret signaling, sonic hedgehog, endothelin-3 (END3) and endothelin receptor B signaling and many others. Figure 2 above shows the location of the main factors guiding the migration of the developing ENS. Migration generally works through GDNF/Ret signaling and endothelin-3/endothelin receptor B signaling. GDNF is primarily expressed in the foregut, GDNF and endothelin 3 are both high in the mid gut, and endothelin 3 is highly expressed in the hindgut. The migrating neural crest cells express certain receptors, such as Ret or endothelin receptor B, which then assists in the migration of the neural crest cells to the proper part of the gut. For instance, neural crest cells expressing Ret will be more attracted to the foregut because Ret will bind the GDNF that is expressed in the foregut. This is just one example of many mechanisms by which migrating neural crest cells find their final destination.

One disease that occurs from disrupted ENS formation is Hirschprung’s disease. This disease is characterized by a lack of enteric neurons in the hindgut, referred to as colonic aganglionosis. This lack of neurons in the colon results in accumulation of intestinal contents in the hind gut. This disease is usually diagnosed shortly after birth when the baby fails to make a bowel movement within the first 48 hours. The smooth muscle within the wall of the gut is unable to relax due to the lack of neuronal instruction, and thus intestinal contents cannot pass through. The exact cause is unknown, but it can occur with genetic mutations in ENS development genes, such GDNF, sonic hedgehog and endothelin-3. It is thought that this disease is caused by a disruption in the migration of neural crest cells where they do not migrate throughout the length of the GI tract. Changes in the aforementioned genes result in a lack of migration of neural crest cells, indicating that that is one plausible causes of Hirschprung’s.

Zebrafish,a common model organism (see previous blog post on Zebrafish), have been used extensively to research the etiology of Hirschprung’s, as well as the overall development of the ENS. Zebrafish have been used to discover genetic targets of Hirschprung’s disease (for review see [7]). Figure 3 below(modifed from Heaune and Pachnis, 2007) shows some of the common ENS phenotypes and what mutations are known to cause them. For instant, a reduction of Ret in zebrafish results in a lack of neurons within the entire gut. Mutations in Ret account for 15-35% of patients with non familial Hirschprung’s, and 50% of patients with familial Hirschprung’s.Slide3

The enteric nervous system is a very important, but frequently understated component of the nervous system and the gastrointestinal system is currently a hot topic in general society. For instance, there is a lot of buzz going around about the importance of gut flora and microbiota and their connection to overall physical and mental health. I hope that you can now go forth into the world with a better understanding of the development of the ENS and what happens when development goes awry. In a later installment I will go on to discuss the connection between gut microbiota, childhood development, and autism, so stay tuned!


  1. Bayliss, W. M., and E. H. Starling. “The Movements and the Innervation of the Large Intestine.” The Journal of Physiology1-2 (1900): 107–118. Print.
  1. Bayliss, W. M., and E. H. Starling. “The Movements and Innervation of the Small Intestine.” The Journal of Physiology2 (1899): 99–143. Print.
  1. Burns AJ, Champeval D, Le Douarin NM. Sacral neural crest cells colonise aganglionic hindgut in vivo but fail to compensate for lack of enteric ganglia. Dev Biol. 2000;219:30–43.
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  1. Anderson RB, Newgreen DF, Young HM. Neural Crest and the Development of the Enteric Nervous System. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-. Available from: http://www.ncbi.nlm.nih.gov/books/NBK6273/
  1. Huanue T, Pachnis V. Enteric nervous system development and Hirschsprung’s disease: advances in genetic and stem cell studies. Nat Rev Neurosci. 2007: 8(6):466-479.
  1. Golsharifi M. “The development of the enteric nervous system and its role in Hirschsprung’s disease”. ProJMed, July 2 2015. Online.
  1. Roth G, Dicke U. Evolution of the brain and intelligence. Trends in Cognitive Sciences. 2005: 9(5). doi:10.1016/j.tics.2005.03.005.
  1. Tek-en, Goran. Layers of the Alimentary Canal. The wall of the alimentary canal has four basic tissue layers: the mucosa, submucosa, muscularis, and serosa. Digital image. Wikimedia Commons. N.p., n.d. Web. <https://commons.wikimedia.org/wiki/File:Layers_of_the_GI_Tract_english.svg&gt;.
  1. Yntema CL, Hammond WS. The origin of intrinsic ganglia of trunk viscera from vagal neural crest in the chick embryo. J Comp Neurol. 1954;101:515–541.



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