Adriano Flora

Baylor College of Medicine, Houston, TX, United States

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Publications (6)97.79 Total impact

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    ABSTRACT: Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by expansion of a translated CAG repeat in Ataxin-1 (ATXN1). To determine the long-term effects of exercise, we implemented a mild exercise regimen in a mouse model of SCA1 and found a considerable improvement in survival accompanied by up-regulation of epidermal growth factor and consequential down-regulation of Capicua, which is an ATXN1 interactor. Offspring of Capicua mutant mice bred to SCA1 mice showed significant improvement of all disease phenotypes. Although polyglutamine-expanded Atxn1 caused some loss of Capicua function, further reduction of Capicua levels--either genetically or by exercise--mitigated the disease phenotypes by dampening the toxic gain of function. Thus, exercise might have long-term beneficial effects in other ataxias and neurodegenerative diseases.
    Science 11/2011; 334(6056):690-3. · 31.20 Impact Factor
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    ABSTRACT: The proneural, basic helix-loop-helix transcription factor Atoh1 governs the development of numerous key neuronal subtypes, such as cerebellar granule and brainstem neurons, inner ear hair cells, and several neurons of the proprioceptive system, as well as diverse nonneuronal cell types, such as Merkel cells and intestinal secretory lineages. However, the mere handful of targets that have been identified barely begin to account for Atoh1's astonishing range of functions, which also encompasses seemingly paradoxical activities, such as promoting cell proliferation and medulloblastoma formation in the cerebellum and inducing cell cycle exit and suppressing tumorigenesis in the intestine. We used a multipronged approach to create a comprehensive, unbiased list of over 600 direct Atoh1 target genes in the postnatal cerebellum. We found that Atoh1 binds to a 10 nucleotide motif (AtEAM) to directly regulate genes involved in migration, cell adhesion, metabolism, and other previously unsuspected functions. This study expands current thinking about the transcriptional activities driving neuronal differentiation and provides a framework for further neurodevelopmental studies.
    Proceedings of the National Academy of Sciences 02/2011; 108(8):3288-93. · 9.81 Impact Factor
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    ABSTRACT: Granule neuron precursors (GNPs) are the most actively proliferating cells in the postnatal nervous system, and mutations in pathways that control the GNP cell cycle can result in medulloblastoma. The transcription factor Atoh1 has been suspected to contribute to GNP proliferation, but its role in normal and neoplastic postnatal cerebellar development remains unexplored. We show that Atoh1 regulates the signal transduction pathway of Sonic Hedgehog, an extracellular factor that is essential for GNP proliferation, and demonstrate that deletion of Atoh1 prevents cerebellar neoplasia in a mouse model of medulloblastoma. Our data shed light on the function of Atoh1 in postnatal cerebellar development and identify a new mechanism that can be targeted to regulate medulloblastoma formation.
    Science 12/2009; 326(5958):1424-7. · 31.20 Impact Factor
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    ABSTRACT: Mice lacking the proneural transcription factor Math1 (Atoh1) lack multiple neurons of the proprioceptive and arousal systems and die shortly after birth from an apparent inability to initiate respiration. We sought to determine whether Math1 was necessary for the development of hindbrain nuclei involved in respiratory rhythm generation, such as the parafacial respiratory group/retrotrapezoid nucleus (pFRG/RTN), defects in which are associated with congenital central hypoventilation syndrome (CCHS). We generated a Math1-GFP fusion allele to trace the development of Math1-expressing pFRG/RTN and paratrigeminal neurons and found that loss of Math1 did indeed disrupt their migration and differentiation. We also identified Math1-dependent neurons and their projections near the pre-Bötzinger complex, a structure critical for respiratory rhythmogenesis, and found that glutamatergic modulation reestablished a rhythm in the absence of Math1. This study identifies Math1-dependent neurons that are critical for perinatal breathing that may link proprioception and arousal with respiration.
    Neuron 11/2009; 64(3):341-54. · 15.77 Impact Factor
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    ABSTRACT: Purpose: , Congenital neuro-respiratory disorders including Congenital Central Hypoventilation Syndrome (CCHS) cause substantial morbidity and mortality in childhood. The respiratory rhythm is modulated by multiple hindbrain nuclei, but the identities, function, and origins for many of these lineages are unknown. Mice that lack the proneural transcription factor Math1 die soon after birth from central apnea. We hypothesized that Math1 expression is required for the development of neurons critical for respiration and that Math1-lineal neurons project to nuclei known to modulate respiration. Methods: , We utilized a combination of physiological, fate mapping, and projection labeling techniques to investigate our hypotheses. Physiological analysis was derived from E18.5 murine embryos utilizing standard brain stem-spinal cord preparations and the impact of neuromodulators on the respiratory rhythm tested. We generated a new Math1-GFP fusion allele to identify neurons actively expressing Math1 in vivo and a novel progesterone inducible Math1Cre*PR allele for fate mapping. The latter allele also allowed specific Math1-projection labeling in conjunction with a reporter mouse expressing membrane-bound GFP. Results: , Math1-null mice die owing to a defect localized to the medulla and bathing with a glutamate reuptake inhibitor reestablishes the respiratory rhythm. With the Math1-GFP allele we identified a novel population of neurons that activate Math1 intraparenchymally. These neurons co-express Phox2b and Lbx1 and migrate to the position of parafacial respiratory group/retrotrapezoid nucleus (pFRG/RTN) where they co-express NK1R. In the absence of Math1, pFRG/RTN neurons fail to develop appropriately. Lastly, we found that neurons expressing Math1 at E10.5 send projections to the preBtzinger complex, the central pattern generator for the respiratory rhythm. Conclusions: , Math1 is required for proper development of the pFRG/RTN and Math1-lineal neurons send projections to the preBtzinger complex. Physiological data supports that Math1 glutamatergic neurons provide a vital excitatory drive for respiration at birth. Patients and mouse models of CCHS are known to lose the pFRG/RTN raising the possibility that it is critical for respiration. This study provides insight about the developmental lineage of these neurons, their dependency on Math1, and reveals the critical role of Math1 for development of multiple components of the respiratory network. KAA, MFR, and JR contributed equally to this work
    2009 American Academy of Pediatrics National Conference and Exhibition; 10/2009
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    ABSTRACT: Proneural factors represent <10 transcriptional regulators required for specifying all of the different neurons of the mammalian nervous system. The mechanisms by which such a small number of factors creates this diversity are still unknown. We propose that proteins interacting with proneural factors confer such specificity. To test this hypothesis we isolated proteins that interact with Math1, a proneural transcription factor essential for the establishment of a neural progenitor population (rhombic lip) that gives rise to multiple hindbrain structures and identified the E-protein Tcf4. Interestingly, haploinsufficiency of TCF4 causes the Pitt-Hopkins mental retardation syndrome, underscoring the important role for this protein in neural development. To investigate the functional relevance of the Math1/Tcf4 interaction in vivo, we studied Tcf4(-/-) mice and found that they have disrupted pontine nucleus development. Surprisingly, this selective deficit occurs without affecting other rhombic lip-derived nuclei, despite expression of Math1 and Tcf4 throughout the rhombic lip. Importantly, deletion of any of the other E-protein-encoding genes does not have detectable effects on Math1-dependent neurons, suggesting a specialized role for Tcf4 in distinct neural progenitors. Our findings provide the first in vivo evidence for an exclusive function of dimers formed between a proneural basic helix-loop-helix factor and a specific E-protein, offering insight about the mechanisms underlying transcriptional programs that regulate development of the mammalian nervous system.
    Proceedings of the National Academy of Sciences 09/2007; 104(39):15382-7. · 9.81 Impact Factor

Publication Stats

232 Citations
97.79 Total Impact Points

Institutions

  • 2007–2011
    • Baylor College of Medicine
      • • Department of Molecular & Human Genetics
      • • Program in Developmental Biology
      Houston, TX, United States
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States