The enteric nervous system (ENS) is represented by a complex network of neurons, glial and other cells within the wall of the digestive tract. ENS is responsible for numerous, vital functions in our body. Thus, ENS regulates motility of the digestive tract, secretion into the intestinal lumen, exchange of fluid and electrolytes through the mucosa, as well as mucosal perfusion. In order to perform these important functions, proper embryonic development of ENS is necessary. ENS cells are derived from precursor cells of the neural crest (NCCs - neural crest cells). Two cell populations that contribute to the largest number of future ENS cells are the vagal and sacral NCCs. Vagal NCCs enter the primitive gut tube in the region of the future esophagus (foregut), and begin their migration, through the midgut towards the hindgut and the future anal region. Sacral NCCs enter the hindgut region following the extrinsic nerve fibers and continue their migration rostrally, towards vagal NCCs. Along with the migration process, these cells undergo other important processes, such as proliferation, neuro-glial differentiation, gangliogenesis, axonal pathway formation and synaptogenesis. All these processes are strictly regulated by numerous signaling pathways, which are still being actively researched. Modern lineage tracing and other technologies, that enabled following of individual precursor cells through their development pathways, will significantly contribute to the better understanding of development of ENS. This may have repercussions in improving the diagnosis and treatment of some developmental (Hirschsprung disease) and other ENS disorders.

The enteric nervous system (ENS) provides intrinsic innervation of the gastrointestinal tract and is the largest and most complex part of the peripheral nervous system. Its functions are vital for life and include control of motility of the digestive tract, secretion, as well as fluid and electrolyte exchange through the intestinal mucosa. ENS is capable of performing most of these functions completely autonomously. A large number of developmental and genetic studies of the most common congenital disease of the ENS, Hischsprung' s disease, has made a major contribution to the understanding of the embryonic development of the ENS. ENS cells raise from the vagal (mostly) and sacral region of the neural crest. These precursor cells migrate along the primitive gut in opposite directions, in order to colonize the entire gut. Proliferation, migration, neuro-glial differentiation, and other processes through which precursor cells of the ENS undergo, are regulated by various signaling pathways. Some of the most important molecules that participate in the regulation of the proper development of the ENS are GDNF (Glial Derived Neurotrophic Fatcor) and its receptor RET (REarranged during Transfection), endothelin 3 and its receptor EDNRB (endothelin receptor type B), transcription factors SOX10 (SRY-box transcription factor 10), PHOX2B (Paired-like Homeobox 2B), morphogens such as BMP 2 and 4 (Bone Morphogenic Proteins) and others. Although our knowledge about control of the development of the ENS has increased significantly in recent years, complexity of structure and function of the ENS requires further research. This review summarizes our current understanding of the most important regulatory mechanisms and signaling pathways involved in the development of the ENS.