Transcription-Factor-Dependent Control of Adult Hippocampal Neurogenesis

Abstract

Adult-generated dentate granule neurons have emerged as major contributors to hippocampal plasticity. New neurons are generated from neural stem cells through a complex sequence of proliferation, differentiation, and maturation steps. Development of the new neuron is dependent on the precise temporal activity of transcription factors, which coordinate the expression of stage-specific genetic programs. Here, we review current knowledge in transcription factor-mediated regulation of mammalian neural stem cells and neurogenesis and will discuss potential mechanisms of how transcription factor networks, on one hand, allow for precise execution of the developmental sequence and, on the other hand, allow for adaptation of the rate and timing of adult neurogenesis in response to complex stimuli. Understanding transcription factor-mediated control of neuronal development will provide new insights into the mechanisms underlying neurogenesis-dependent plasticity in health and disease.

Figure 1.

Model of the adult hippocampal neurogenic lineage. (A) Expression of commonly used markers for distinct developmental stages. (B) Expression pattern of transcription factors, for which a function in the adult hippocampal neurogenic lineage has been determined or proposed. Note that the precise expression pattern of nuclear factor 1 X-type (NFIX), Bmi, FoxOs, and Hmga2 in the adult hippocampal neurogenic lineage has not been fully established; for these transcription factors, the expression pattern is assumed, based on their proposed function. In the case of the Notch-signal transducer RBPJk, the activity of the Notch/RBPJk pathway is shown. REST, Repressor element 1–silencing transcription; pCREB, phosphorylated CREB; DCX, doublecortin.

Figure 2.

Emerging mechanisms underlying transcription factor-dependent control of adult hippocampal neurogenesis. (A) Sequential occupancy of enhancers and promoters of key differentiation genes by stage-specific transcription factors during lineage progression. The neural-stem-cell-specific transcription factor X (TF-X) activates the stage-specific gene-expression program, and additionally primes the cell to express the developmental program of the following step, in this case, a neuron-specific gene-expression program. On lineage progression, the neuron-specific transcriptional regulator transcription factor Y (TF-Y) binds to an overlapping set of enhancers and promoters. TF-Y exerts negative feedback on the gene-expression programs of the preceding developmental step (i.e., the stem-cell program), and activates the neuronal gene-expression program. (B) Cross-regulatory loops provide the advantage of a self-regulatory transcriptional network, which on one hand is largely self-sufficient and robust, but on the other hand can be quickly dissolved by dysregulation of a single factor to induce lineage progression. In this example, transcription factors A, B, and C regulate each other and cooperatively regulate stage-specific gene-expression programs. Cross-regulation results in robust levels of all three transcription factors and consequently in stable stage-specific gene expression. Dysregulation of the transcription factor A by a lineage progression signal results in lowered levels of all three transcriptional regulators. As a consequence, the stage-specific gene-expression program cannot be maintained and cells undergo lineage progression. (C) Core regulatory transcription factor networks cooperatively control stage-specific gene-expression programs. The incorporation of transcriptional signal transducers into these networks allows wiring of the activity of extrinsic signals into gene-expression programs.