The development of multicellular organisms is driven by the activity of stem cell populations. Stem cells reside in microenvironments or niches that carefully balance the processes of cell self-renewal and differentiation. Disruptions in this balance can lead to severe developmental abnormalities, including congenital defects and cancer. Uncovering the processes regulating stem cell behavior will lead to more effective treatments and cures for such conditions. An understanding of this regulation is also necessary to fully harness the enormous therapeutic potential offered by stem cell-based strategies for tissue and organ regeneration. Our long-term objectives include identifying and characterizing the factors involved in maintaining the stem cell niche and controlling stem cell proliferation. To achieve these goals, we will take advantage of the easily accessible and highly regenerative stem cell populations of the model plant Arabidopsis thaliana. Our first specific aim is to identif key transcription factors that maintain stem cell function by repressing differentiation-promoting genes. We have identified the Arabidopsis histone deacetylase HDA19 as an indispensable repressor of fate- specifying genes in the reproductive shoot apical meristem (SAM), a stem cell niche responsible for initiating flowers. Moreover, we have elucidated the precise genomic regions HDA19 occupies to putatively repress fate- specifying genes during reproductive development. In our first aim, we will use this information to perform unbiased, high throughput yeast one-hybrid assays to identify DNA-binding transcription factors that physically recruit HDA19 to these regions. We will then functionally characterize these factors to identify those that are essential for preserving the integrity of the stem cell niche. In our second aim, we will investigate the signals that control stem cell proliferation by studying how the reproductive SAM enters a reversibly quiescent state late in development. Through the use of tissue grafts, we will assess whether this quiescence is triggered by an internal property of the stem cells themselves or by surrounding tissues, such as developing embryos. We will also determine, at the transcriptomic level, the changes in gene expression that occur in the SAM as it approaches quiescence due to age and/or reproductive output. By manipulating the expression of these quiescence-associated genes, we expect to controllably alter the duration of the plant reproductive stage. Collectively, our approaches will characterize the signals and molecular mechanisms that modulate stem cell proliferation and niche maintenance in multicellular eukaryotes.
Disruptions to stem cell function can lead to a variety of abnormalities, including congenital defects and the initiation and progression of cancer. A more complete understanding of stem cell regulation is not only required to optimize prevention and treatment of these conditions, but also to fully realize the tremendous potential of stem cell-based regenerative medicine. This proposal has significant public health relevance because it will contribute greatly to our understanding of stem cell regulation by exploiting the technically amenable and highly regenerative stem cell populations of Arabidopsis.
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| Carey, Nicholas S; Krogan, Naden T (2017) The role of AUXIN RESPONSE FACTORs in the development and differential growth of inflorescence stems. Plant Signal Behav 12:e1307492 |
| Krogan, Naden T; Marcos, Danielle; Weiner, Aaron I et al. (2016) The auxin response factor MONOPTEROS controls meristem function and organogenesis in both the shoot and root through the direct regulation of PIN genes. New Phytol 212:42-50 |
