Browsing by Author "Ware, Stephanie"

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    The Role of Inflammatory Signaling Pathways in TET2-Deficient Hematological Malignancies
    (2024-08) Burns, Sarah Sterling; Kapur, Reuben; Davé, Utpal; Ware, Stephanie; Herbert, Brittney-Shea
    Loss of the TET2 gene, which is commonly mutated in the pre-leukemic condition clonal hematopoiesis of indeterminate potential (CHIP) and hematological malignancies, dysregulates inflammation, including the interleukin-1 (IL-1) and interleukin-6 (IL-6) pathways. As TET2 mutations are often present in hematopoietic stem and progenitor cells, dysregulation of these pathways may contribute to leukemogenesis and may catalyze the progression of pre-leukemic states, such as CHIP, to malignancy. Tet2-/- mice exhibit splenomegaly, myeloid expansion, and myeloid malignancy. To investigate the effects of inactivation of IL-1 receptor, type 1 (Il-1r1) and Il-6 on Tet2-deficient mature and immature hematopoietic cells, Tet2-/-;Il-1r1-/- and Tet2-/-;Il-6-/- mice were generated. Interestingly, Il-1r1 loss rescued the leukemic phenotypes associated with Tet2 inactivation, including expansion of myeloid cells, suppression of lymphoid cells, and restoration of spleen size. These phenotypes were recapitulated with competitive transplant, suggesting that IL-1R1 exerts a cell autonomous role. Mice transplanted with Tet2-/-;Il-1r-/- bone marrow cells exhibited differential regulation of specific myeloid and lymphoid subpopulations. At the stem-cell level, the frequencies of early myeloid Lin-;c- Kit+, early lymphoid Lin-;Sca1+ progenitors, and multipotent progenitor populations 2 and 3/4 were corrected, and a pronounced and reciprocal switch in the levels of Lin-;c- Kit+ and Lin-;Sca1+ cells was detected. Aged Tet2-/-;Il-1r-/- mice retained some of these phenotypes. Acute myeloid leukemia with higher IL-1R1 expression had reduced survival, indicating potential clinical implications. Similar to Tet2-/-;Il-1r1-/- mice, Tet2-/- ;Il-6-/- mice showed correction of myeloid cell expansion and lymphocyte suppression; however, they also demonstrated a significant increase in long-term hematopoietic stem cells and possible splenic extramedullary hematopoiesis, highlighting unique roles of IL- 6 in the pre-leukemic context. Collectively, these findings suggest that IL-1R1- and IL-6- dependent signaling exhibit overlapping functions but also have distinct roles in leukemogenesis that may have important implications for the clinical management of CHIP and hematological malignancies.
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    Zic3 enables bimodal regulation of tyrosine hydroxylase expression in olfactory bulb and midbrain-derived neurons
    (Springer Nature, 2025-04-11) Bhaskar, Smitha; Gowda, Jeevan; Hegde, Akshay; Thumu, Surya Chandra Rao; Banerjee, Shreetama; Bellchambers, Helen M.; Ramanan, Narendrakumar; Sala, Paloma Merchan; Campbell, Kenneth; Ware, Stephanie; Prasanna, Jyothi; Kumar, Anujith; Medical and Molecular Genetics, School of Medicine
    Tyrosine hydroxylase (TH) is the rate-limiting enzyme involved in the biosynthesis of catecholamines such as dopamine, norepinephrine, and epinephrine expressed in various regions of the brain, including the olfactory bulb (OB) and midbrain (MB). Previous studies demonstrated Zinc Finger transcription factor of the Cerebellum 3 (ZIC3) to regulate forebrain development, and Zic1/Zic3 compound mutant mice displayed reduced OB size. However, the precise role of ZIC3 in TH regulation remains elusive. In this study, we attempted to understand the role of ZIC3 in TH regulation and its underlying mechanism. While loss of function of Zic3 in OB-derived neurons led to down-regulation of TH expression, it could be rescued by over-expression of shRNA-resistant Zic3. Immunohistochemistry of OB of Zic3 null mice showed a similar reduction in expression of TH. Promoter of TH lacks the consensus ZIC3 binding region, and mechanistic insights revealed ZIC3 to regulate TH expression by interacting with ER81, a known TH regulator. ZIC3 interaction with ER81 is indispensable for ER81 binding to the Th promoter, and it fine-tunes ER81-mediated Th regulation in OB. In MB, where TH levels are highest after birth, ZIC3 regulates TH expression both in vitro and in vivo. TH was significantly reduced in P0 Zic3 null mice, as well as in Zic3 shRNA stereotactically delivered in 7-month-old mice. Mechanistically, in the absence of ER81 in MB, ZIC3 chooses an alternative approach of binding to Pitx3 promoter-a Dopaminergic (DA) fate determinant. Under the ectopic expression of ER81 in MB derived neurons, the propensity of ZIC3 binding to Pitx3 promoter is compromised, and its occupancy on Th promoter encompassing ER81 binding site is established, finally culminating in desired TH expression. Together, these findings reveal a unique ZIC3-mediated bimodal regulation of TH in OB and MB derived neurons.