| 1. |
- Hellwig, Malte, et al.
(författare)
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TCF4 (E2-2) harbors tumor suppressive functions in SHH medulloblastoma
- 2019
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 137:4, s. 657-673
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Tidskriftsartikel (refereegranskat)abstract
- The TCF4 gene encodes for the basic helix–loop–helix transcription factor 4 (TCF4), which plays an important role in the development of the central nervous system (CNS). Haploinsufficiency of TCF4 was found to cause Pitt-Hopkins syndrome (PTHS), a severe neurodevelopmental disorder. Recently, the screening of a large cohort of medulloblastoma (MB), a highly aggressive embryonal brain tumor, revealed almost 20% of adult patients with MB of the Sonic hedgehog (SHH) subtype carrying somatic TCF4 mutations. Interestingly, many of these mutations have previously been detected as germline mutations in patients with PTHS. We show here that overexpression of wild-type TCF4 in vitro significantly suppresses cell proliferation in MB cells, whereas mutant TCF4 proteins do not to the same extent. Furthermore, RNA sequencing revealed significant upregulation of multiple well-known tumor suppressors upon expression of wild-type TCF4. In vivo, a prenatal knockout of Tcf4 in mice caused a significant increase in apoptosis accompanied by a decreased proliferation and failed migration of cerebellar granule neuron precursor cells (CGNP), which are thought to be the cells of origin for SHH MB. In contrast, postnatal in vitro and in vivo knockouts of Tcf4 with and without an additional constitutive activation of the SHH pathway led to significantly increased proliferation of CGNP or MB cells. Finally, publicly available data from human MB show that relatively low expression levels of TCF4 significantly correlate with a worse clinical outcome. These results not only point to time-specific roles of Tcf4 during cerebellar development but also suggest a functional linkage between TCF4 mutations and the formation of SHH MB, proposing that TCF4 acts as a tumor suppressor during postnatal stages of cerebellar development.
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| 2. |
- O'Rourke, Joseph G., et al.
(författare)
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Venus, the Planet : Introduction to the Evolution of Earth's Sister Planet
- 2023
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Ingår i: Space Science Reviews. - : Springer. - 0038-6308 .- 1572-9672. ; 219:1
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Forskningsöversikt (refereegranskat)abstract
- Venus is the planet in the Solar System most similar to Earth in terms of size and (probably) bulk composition. Until the mid-20th century, scientists thought that Venus was a verdant world-inspiring science-fictional stories of heroes battling megafauna in sprawling jungles. At the start of the Space Age, people learned that Venus actually has a hellish surface, baked by the greenhouse effect under a thick, CO2-rich atmosphere. In popular culture, Venus was demoted from a jungly playground to (at best) a metaphor for the redemptive potential of extreme adversity. However, whether Venus was much different in the past than it is today remains unknown. In this review, we show how now-popular models for the evolution of Venus mirror how the scientific understanding of modern Venus has changed over time. Billions of years ago, Venus could have had a clement surface with water oceans. Venus perhaps then underwent at least one dramatic transition in atmospheric, surface, and interior conditions before present day. This review kicks off a topical collection about all aspects of Venus's evolution and how understanding Venus can teach us about other planets, including exoplanets. Here we provide the general background and motivation required to delve into the other manuscripts in this collection. Finally, we discuss how our ignorance about the evolution of Venus motivated the prioritization of new spacecraft missions that will rediscover Earth's nearest planetary neighbor-beginning a new age of Venus exploration.
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| 3. |
- Widemann, Thomas, et al.
(författare)
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Venus Evolution Through Time : Key Science Questions, Selected Mission Concepts and Future Investigations
- 2023
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Ingår i: Space Science Reviews. - : SPRINGER. - 0038-6308 .- 1572-9672. ; 219:7
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Forskningsöversikt (refereegranskat)abstract
- In this work we discuss various selected mission concepts addressing Venus evolution through time. More specifically, we address investigations and payload instrument concepts supporting scientific goals and open questions presented in the companion articles of this volume. Also included are their related investigations (observations & modeling) and discussion of which measurements and future data products are needed to better constrain Venus' atmosphere, climate, surface, interior and habitability evolution through time. A new fleet of Venus missions has been selected, and new mission concepts will continue to be considered for future selections. Missions under development include radar-equipped ESA-led EnVision M5 orbiter mission (European Space Agency 2021), NASA-JPL's VERITAS orbiter mission (Smrekar et al. 2022a), NASA-GSFC's DAVINCI entry probe/flyby mission (Garvin et al. 2022a). The data acquired with the VERITAS, DAVINCI, and EnVision from the end of this decade will fundamentally improve our understanding of the planet's long term history, current activity and evolutionary path. We further describe future mission concepts and measurements beyond the current framework of selected missions, as well as the synergies between these mission concepts, ground-based and space-based observatories and facilities, laboratory measurements, and future algorithmic or modeling activities that pave the way for the development of a Venus program that extends into the 2040s (Wilson et al. 2022).
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