The Timing Mechanism of Gene Expression in Maturing Neurons
Central nervous system (CNS) development results from the interactions between intrinsic genes and extrinsic environment. The process of neuronal development consists of successive developmental stages including proliferation, differentiation, migration, axon extension, dendritogenesis, and formation of functional synapses (Figure 1A). In this developmental sequence, the interplay between genes and environment ensures that each step must occur in the proper timing and sequence. Their successful regulation requires that numerous groups of genes be turned on and off in a timely manner. However, the timing mechanisms of gene expression in maturing neurons are not fully understood.
By using mouse cerebellar granule neurons (CGNs) as a research model, we have identified a novel nuclear factor one (NFI)-regulated temporal switch program linked to dendrite formation. In this program, neuronal mature genes (late expressed synaptogenesis-related genes) are up-regulated and immature genes (early expressed amplification-related genes) are down-regulated during a period of postnatal development window (Figure 1B). One distinguished feature of this program is the NFI temporal occupancy of target gene promoters. We also found that NFI switch program were regulated by resting membrane potential, CaN/NFAT signaling pathway, ETV1 and BDNF etc (Figure 1C). Most interestingly, some neurodevelopmental disorders are associated with particular NFI-regulated 'switch' genes, such as Autism Spectrum Disorders (ASD). Research efforts are focusing on identification and characterization of novel regulators and signaling pathways of NFI-regulated program, and the involvement of disrupted NFI-regulated developmental program in neurodevelopmental disorders.
Ding B, Dobner PR, Mullikin-Kilpatrick D, Wang W, Zhu H, Chow CW, Gronostajski RM and Kilpatrick DL. (2018). BDNF Activates an NFI-Dependent Neurodevelopmental Timing Program By Sequestering NFATc4. Mol Biol Cell. 29(8):975-987 PDF
Leto K, Arancillo M, Becker EB, Buffo A, Chiang C, Ding B, Dobyns WB, Dusart I, Haldipur P, Hatten ME, Hoshino M, Joyner AL, Kano M, Kilpatrick DL, Koibuchi N, Marino S, Martinez S, Millen KJ, Millner TO, Miyata T, Parmigiani E, Schilling K, Sekerková G, Sillitoe RV, Sotelo C, Uesaka N, Wefers A, Wingate RJ, Hawkes R. (2016) Consensus Paper: Cerebellar Development. Cerebellum. Dec;15(6): 789-828 PDF
Ding B, Cave HW, Dobner PR, Kilpatrick DM, Bartsokis M, Zhu H, Chow CW, Gronostajski RM and Kilpatrick DL. (2016) Reciprocal Auto-Regulation by NFI Occupancy and ETV1 Promotes the Developmental Expression of Dendrite-Synapse Genes in Cerebellar Granule Neurons. Mol Biol Cell. 27(9):1488-99 PDF
Ding B. (2015) Gene Expression in Maturing Neurons: Regulatory Mechanisms and Related Neurodevelopmental Disorders. ACTA PHYSIOLOGICA SINICA (Sheng Li Xue Bao). 67(2):113-33. (Invited Review) PDF
Ding B, Wang W, Selvakumar T, Xi HS, Zhu H, Chow CW, Horton JD, Gronostajski RM and Kilpatrick DL. (2013) Temporal Regulation of Nuclear Factor One Occupancy by Calcineurin/NFAT Governs a Voltage-Sensitive Developmental Switch in Late Maturing Neurons. J Neurosci. 33(7):2860-2872 PDF