Transforming Growth Factor β (Tgfβ) and associated signaling effectors are expressed in the forebrain, but little is known about the role of this multifunctional cytokine during forebrain development. Using hippocampal and cortical primary cell cultures of developing mouse brains, this study identified Tgfβ-regulated genes not only associated with cell cycle exit of progenitors but also with adoption of neuronal cell fate. Accordingly, we observed not only an antimitotic effect of Tgfβ on progenitors but also an increased expression of neuronal markers in Tgfβ treated cultures. This effect was dependent upon Smad4. Furthermore, in vivo loss-of-function analyses using Tgfβ2−/−/Tgfβ3−/− double mutant mice showed the opposite effect of increased cell proliferation and fewer neurons in the cerebral cortex and hippocampus. Gata2, Runx1, and Nedd9 were candidate genes regulated by Tgfβ and known to be involved in developmental processes of neuronal progenitors. Using siRNA-mediated knockdown, we identified Nedd9 as an essential signaling component for the Tgfβ-dependent increase in neuronal cell fate. Expression of this scaffolding protein, which is mainly described as a signaling molecule of the β1-integrin pathway, was not only induced after Tgfβ treatment but was also associated with morphological changes of the Nestin-positive progenitor pool observed upon exposure to Tgfβ.
Mutations of leukemia-associated AF9/MLLT3 are implicated in neurodevelopmental diseases, such as epilepsy and ataxia, but little is known about how AF9 influences brain development and function. Analyses of mouse mutants revealed that during cortical development, AF9 is involved in the maintenance of TBR2-positive progenitors (intermediate precursor cells, IPCs) in the subventricular zone and prevents premature cell cycle exit of IPCs. Furthermore, in postmitotic neurons of the developing cortical plate, AF9 is implicated in the formation of the six-layered cerebral cortex by suppressing a TBR1-positive cell fate mainly in upper layer neurons. We show that the molecular mechanism of TBR1 suppression is based on the interaction of AF9 with DOT1L, a protein that mediates transcriptional control through methylation of histone H3 lysine 79 (H3K79). AF9 associates with the transcriptional start site of Tbr1, mediates H3K79 dimethylation of the Tbr1 gene, and interferes with the presence of RNA polymerase II at the Tbr1 transcriptional start site. AF9 expression favors cytoplasmic localization of TBR1 and its association with mitochondria. Increased expression of TBR1 in Af9 mutants is associated with increased levels of TBR1-regulated expression of NMDAR subunit Nr1. Thus, this study identified AF9 as a developmental active epigenetic modifier during the generation of cortical projection neurons.A F9/MLLT3 is one of multiple fusion partners of the histone methyltransferase MLL1 in acute leukemia (1, 2). However, mutations of the AF9/MLLT3 gene alone are not associated with leukemia but are implicated in anterior homeotic transformations during mouse development (3), and in neurodevelopmental diseases, such as mental retardation, epilepsy, and ataxia in human patients (4,5). Little is known about AF9 function in the CNS, although its expression pattern implies a role during development of the forebrain and cerebellum (6). In the mouse forebrain, Af9 is transcribed in the subventricular zone (SVZ), a neurogenic compartment that harbors progenitors for upper layer neurons (7,8). Af9 is also expressed in neurons dispersed over all cortical layers and diverges in this respect from other SVZ markers, such as Svet1 and Cux2 (6). On the molecular level, AF9 mediates transcriptional activation and was classified as a proto-oncogene (9). The AF9 protein interacts with many different factors and has been implicated in different cellular processes (9-11). In the extensive network of interacting proteins, AF9 associates with DOT1L (12, 13), the main enzyme responsible for histone H3 methylation at lysine 79 (14-16). Dot1 is implicated in UV damage repair (17), and affects gene expression in yeast, flies, and mammals (18, 19), whereas histone H3 lysine 79 (H3K79) methylation correlates with gene activation (20) and suppression (21). Following this line, AF9-DOT1L complexes mediate transcriptional activation through increased levels of dimethylated H3K79 (13), but are also capable of transcriptional repression through hypermethyla...
A major barrier to advancing ornithology is the systemic exclusion of professionals from the Global South. A recent special feature, Advances in Neotropical Ornithology, and a shortfalls analysis therein, unintentionally followed a long-standing pattern of highlighting individuals, knowledge, and views from the Global North, while largely omitting the perspectives of people based within the Neotropics. Here, we review current strengths and opportunities in the practice of Neotropical ornithology. Further, we discuss problems with assessing the state of Neotropical ornithology through a northern lens, including discovery narratives, incomplete (and biased) understanding of history and advances, and the promotion of agendas that, while currently popular in the north, may not fit the needs and realities of Neotropical research. We argue that future advances in Neotropical ornithology will critically depend on identifying and addressing the systemic barriers that hold back ornithologists who live and work in the Neotropics: unreliable and limited funding, exclusion from international research leadership, restricted dissemination of knowledge (e.g., through language hegemony and citation bias), and logistical barriers. Moving forward, we must examine and acknowledge the colonial roots of our discipline, and explicitly promote anti-colonial agendas for research, training, and conservation. We invite our colleagues within and beyond the Neotropics to join us in creating new models of governance that establish research priorities with vigorous participation of ornithologists and communities within the Neotropical region. To include a diversity of perspectives, we must systemically address discrimination and bias rooted in the socioeconomic class system, anti-Blackness, anti-Brownness, anti-Indigeneity, misogyny, homophobia, tokenism, and ableism. Instead of seeking individual excellence and rewarding top-down leadership, institutions in the North and South can promote collective leadership. In adopting these approaches, we, ornithologists, will join a community of researchers across academia building new paradigms that can reconcile our relationships and transform science. Spanish and Portuguese translations are available in the Supplementary Material.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.