Spinocerebellar ataxia type 1 (SCA1) is one of nine inherited, typically adult onset, polyglutamine neurodegenerative diseases. To examine whether development impacts SCA1, we used a conditional transgenic mouse model of SCA1 to delay the postnatal expression of mutant ATXN1 until after completion of cerebellar development. Delayed postnatal expression of mutant ATXN1 led to a substantial reduction in severity of disease in adults in comparison with early postnatal gene expression. This was linked to a destabilization of RORalpha, a transcription factor critical for cerebellar development. In SCA1 mice, there was a depletion of RORalpha and a reduction in expression of genes controlled by RORalpha. Partial loss of RORalpha enhanced mutant ATXN1 pathogenicity. Additionally, evidence points to the existence of a complex containing ATXN1, RORalpha, and the RORalpha coactivator Tip60. These studies indicate RORalpha and Tip60 have a role in SCA1 and suggest a mechanism by which compromising cerebellar development contributes to severity of neurodegeneration in an adult.
Mammalian B-cell development can be viewed as a developmental performance with several acts. The acts are represented by checkpoints centered around commitment to the B-lineage and functional Ig gene rearrangement--culminating in expression of the pre-B-cell receptor (pre-BCR) and the BCR. Progression of cells through these checkpoints is profoundly influenced by the fetal liver and adult bone marrow (BM) stromal cell microenvironments. Our laboratory has developed a model of human B-cell development that utilizes freshly isolated/non-transformed human BM stromal cells as an in vitro microenvironment. Human CD34+ hematopoietic stem cells plated in this human BM stromal cell microenvironment commit to the B lineage and progress through the pre-BCR and BCR checkpoints. This human BM stromal cell microenvironment also provides survival signals that prevent apoptosis in human B-lineage cells. Human B-lineage cells exhibit differential expression of Notch receptors and human BM stromal cells express the Notch ligand Jagged-1. These results suggest a potential role for Notch in regulating B-lineage commitment and/or progression through the pre-BCR and BCR checkpoints.
IntroductionNormal lymphoid cell development in the bone marrow and thymus is autonomously regulated by transcription factors that modify patterns of gene expression 1 and externally regulated by the extracellular matrix, stromal cells, and cytokines/chemokines/colony-stimulating factors. 2,3 The fate of developing lymphoid cells is further influenced by the functional balance of proapoptotic and antiapoptotic proteins expressed at specific points in development and the survival signals that are transduced by external cues such as cytokines. 4,5 Induction of apoptosis proceeds through 2 main pathways. The first initiates at cell surface death receptors such as CD95/Fas or the tumor necrosis receptor (the extrinsic pathway). 6,7 The second is triggered by stress, genotoxic agents, or cytokine deprivation (the intrinsic or mitochondrial pathway). 8,9 The biochemical coupling of proapoptotic molecules of the Bcl-2 homology region 3 (BH3) death domain and B-cell lymphoma 2 (Bcl-2) family members to caspase activation and downstream dismantling of cellular structure has been extensively studied in all metazoans. However, caspase activation by itself does not guarantee that apoptotic signals proceed unchecked. Members of the inhibitor of apoptosis (IAP) family of proteins can suppress or delay apoptosis by inhibiting the enzymatic activity of initiator and executioner caspases. 10,11 Whereas activation of initiator (eg, caspases-8, -9, and -10) and executioner (eg, caspases-3, -6, and -7) caspases generally occur by oligomerization of monomeric zymogens and caspase-mediated cleavage, respectively, 12-14 the consequences of inhibition of activated caspases are not completely understood. Although activation of executioner caspases leads to irreversible commitment to death when IAP function is neutralized by second mitochondria-derived activator of caspase (SMAC)/direct IAP binding protein with low PI (DIABLO), loss of mitochondrial function does not. Outer mitochondrial membrane permeabilization (and concomitant translocation of cytochrome C) is not an irreversible event, since caspase inhibition at this juncture can lead to restoration of mitochondrial transmembrane potential (⌬m). 15 This result might be explained by the recent finding that caspase translocation into the mitochondria leads to cleavage of electron transport complexes I and II and further dissolution of mitochondrial integrity. 16 Mammalian B-cell development is an excellent model to study cell fate decisions that culminate in survival or death, since functional immunoglobulin gene rearrangement and appropriate cues from the bone marrow (BM) microenvironment are essential for survival and differentiation. 17 Perturbations in the balance between proapoptotic and antiapoptotic signals can contribute to development of lymphohematopoietic malignancies. 18 During the course of characterizing the role of the mitochondrial pathway in the demise of bone marrow stromal cell-dependent B-lineage acute lymphoblastic leukemia (ALL), we made the unexpected observatio...
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