Adult enteric nervous system in health is maintained by a dynamic balance between neuronal apoptosis and neurogenesis

Subhash Kulkarni, Maria-Adelaide Micci, Jenna Leser, Changsik Shin, Shiue-Cheng Tang, Ya-Yuan Fu, Liansheng Liu, Qian Li, Monalee Saha, Cuiping Li, Grigori Enikolopov, Laren Becker, Nikolai Rakhilin, Michael Anderson, Xiling Shen, Xinzhong Dong, Manish J. Butte, Hongjun Song, E. Michelle Southard-Smith, Raj P. Kapur, Milena Bogunovic, Pankaj J. Pasricha

According to current dogma, there is little or no ongoing neurogenesis in the fully developed adult enteric nervous system. This lack of neurogenesis leaves unanswered the question of how enteric neuronal populations are maintained in adult guts, given previous reports of ongoing neuronal death. Here, we confirm that despite ongoing neuronal cell loss because of apoptosis in the myenteric ganglia of the adult small intestine, total myenteric neuronal numbers remain constant. This observed neuronal homeostasis is maintained by new neurons formed in vivo from dividing precursor cells that are located within myenteric ganglia and express both Nestin and p75NTR, but not the pan-glial marker Sox10. Mutation of the phosphatase and tensin homolog gene in this pool of adult precursors leads to an increase in enteric neuronal number, resulting in ganglioneuromatosis, modeling the corresponding disorder in humans. Taken together, our results show significant turnover and neurogenesis of adult enteric neurons and provide a paradigm for understanding the enteric nervous system in health and disease.