Cell Fate

In neurodegenerative disorders caused by polyglutamine (polyQ) expansion, polyQ toxicity is thought to trigger a linear cascade of successive degenerative events leading to neuronal death. To understand how neurons cope with polyQ toxicity, we studied a Spinocerebellar ataxia 7 (SCA7) mouse which expresses polyQ-expanded ATXN7 only in rod photoreceptors. We show that in response to polyQ toxicity, SCA7 rods go through a range of radically different cell fates, including apoptotic and non-apoptotic cell death, cell migration, morphological transformation into a round cell or, most remarkably, cell division. The temporal profile of retinal remodeling indicates that some degenerative pathways are triggered early in the disease but decline later on, while others worsen progressively. Retinal remodeling results in a relative maintenance of photoreceptor population, but does not preserve the retinal function. Rod responses to proteotoxicity correlate with the nature, level and ratio of mu...

This article addresses the physical mechanics of gametogenesis in vascular plants. The earliest events that initiate reproductive differentiation in the land plants are not well understood. How are the few cells that initiate reproductive differentiation specified and how is that information translated into action at the cellular level? In this article I propose a physical mechanism that resolves the problem of spatial targeting without invoking dependence on diffusible morphogens or other external signals. I suggest that the initiation of archesporial differentiation can instead be attributed to the confluence of organ geometry, surficial topography, and the physical mechanics of sporangial growth, resulting in the spontaneous emergence of an isotropic singularity that locates and precipitates archesporial differentiation. In discussing the logic of single-cell target selection and the limits of stochastic molecular signaling I propose that the sporangium would be better understood as a pressurized stress-mechanical lens that focuses turgor-generated growth forces on a central location, generating a physical singularity that locates and specifies the cell or cells that become the archesporium and initiates their transition from somatic proliferation to reproductive differentiation.

The SOX (sex-determining region [SRY]-type high mobility group [HMG] box) family of transcription factors play key roles in determining cell fate during organ development. In this study, we have identified a new human SOX gene, SOX13, as encoding the type 1 diabetes autoantigen, islet cell antigen 12 (ICA12). Sequence analysis showed that SOX13 belongs to the class D subgroup of SOX transcription factors, which contain a leucine zipper motif and a region rich in glutamine. SOX13 autoantibodies occurred at a significantly higher frequency among 188 people with type 1 diabetes (18%) than among 88 with type 2 diabetes (6%) or 175 healthy control subjects (4%). Deletion mapping of the antibody epitopes showed that the autoantibodies were primarily directed against an epitope requiring the majority of the protein. SOX13 RNA was detected in most human tissues, with the highest levels in the pancreas, placenta, and kidney. Immunohistochemistry on sections of human pancreas identified SOX13...

Resident stem cells or somatic stem cells (SSCs), are a population of undifferentiated cells within a differentiated organ and in a specialized cell. These cells participate in the regulation of homeostasis and tissue repair. Somatic stem cells are self-renewing and can be activated to multiply and differentiate as needed. They are identified in many tissues, including the heart, blood, muscle, skin, and brain. Extensive preclinical and clinical studies have demonstrated the functional and structural regeneration capabilities of these SSCs, such as mesenchymal stromal stem cells, hematopoietic stem cells, bone marrow-derived mononuclear cells, and resident. Somatic stem cells are used to treat disorders of the brain, pancreas, eyes, and heart. Organoids are in vitro cultured 3D structures that outline important aspects of organs in vivo. They derived from SSCs benefit from the cell-driven process of tissue regeneration and can be created directly from the diseased or healthy epithelium of many organs. Among the various SSCs, mesenchymal stem cells, especially those derived from bone marrow and adipose tissue, may be a treatment for diabetic retinopathy. These cells exert their therapeutic effects through paracrine mechanisms. In addition to secretory proteins, SSCs release extracellular vesicles that send their contents to target cells. One of the most promising applications of these vesicles with SSCs is cancer therapy. Furthermore, SSC-extracellular vesicles can be modified to improve targeted drug delivery. The ease of use and therapeutic effects of SSCs have made them candidates for cellular therapeutics. In this chapter, the concept of SSCs and SSC therapy, the use of SSCs, their applications, and their relationship with diseases will be discussed.

The matrix metalloproteinase (MMP) stromelysin-3 (ST3) was originally discovered as a gene whose expression was associated with human breast cancer carcinomas and with apoptosis during organogenesis and tissue remodeling. It has been shown previously, in our studies as well as those by others, that ST3 mRNA is highly upregulated during apoptotic tissue remodeling during Xenopus laevis metamorphosis. Using a function-blocking antibody against the catalytic domain of Xenopus ST3, we demonstrate here that ST3 protein is specifically expressed in the cells adjacent to the remodeling extracellular matrix (ECM) that lies beneath the apoptotic larval intestinal epithelium in X. laevis in vivo, and during thyroid hormone–induced intestinal remodeling in organ cultures. More importantly, addition of this antibody, but not the preimmune antiserum or unrelated antibodies, to the medium of intestinal organ cultures leads to an inhibition of thyroid hormone–induced ECM remodeling, apoptosis of t...

Hairy-related proteins include the Drosophila Hairy and Enhancer of Split proteins and mammalian Hes proteins. These proteins are basic helix-loop-helix (bHLH) transcriptional repressors that control cell fate decisions such as neurogenesis or myogenesis in both Drosophila melanogaster and mammals. Hairy-related proteins are site-specific DNA-binding proteins defined by the presence of both a repressor-specific bHLH DNA binding domain and a carboxyl-terminal WRPW (Trp-Arg-Pro-Trp) motif. These proteins act as repressors by binding to DNA sites in target gene promoters and not by interfering with activator proteins, indicating that these proteins are active repressors which should therefore have specific repression domains. Here we show the WRPW motif to be a functional transcriptional repression domain sufficient to confer active repression to Hairy-related proteins or a heterologous DNA-binding protein, Ga14. This motif was previously shown to be necessary for interactions with Gro...

NOTCH signaling is an evolutionarily conserved signaling pathway that regulates cell fate during development and postnatal life. It has been increasingly linked to carcinogenesis, although its role in cancer seems to be highly context and tissue specific. Although NOTCH signaling is required for lung development, little is known about its role in lung cancer. In this study, we show that NOTCH signaling, as measured by the γ-secretase cleavage product NIC-1, is active in both normal human and lung tumor samples; however, downstream NOTCH readouts (i.e., HES-1 and HES-5) are elevated in lung tumors. Levels of NOTCH signaling components in primary human lung cells reflect observations in tissue samples, yet lung tumor cell lines showed little NOTCH signaling. Because oxygen concentrations are important in normal lung physiology and lung tumors are hypoxic, the effect of low oxygen on these lung tumor cell lines was evaluated. We found that hypoxia dramatically elevates NOTCH signaling ...

We have recently identified Np9 as a novel nuclear protein produced by the human endogenous retrovirus K and were able to document the exclusive presence of np9 transcript in tumors and transformed cells. With the aim of studying whether Np9 has a role in tumorigenesis, a systematic search for interacting proteins was performed. Here, we identify the RING-type E3 ubiquitin ligase LNX (ligand of Numb protein X) as an Np9-interacting partner. We furthermore show that the interaction involves N- and C-terminal domains of both proteins and can affect the subcellular localization of LNX. LNX has been reported to target the cell fate determinant and Notch antagonist Numb for proteasome-dependent degradation, thereby causing an increase in transactivational activity of Notch. We document that LNX-interacting Np9, like Numb, is unstable and degraded via the proteasome pathway and that ectopic Numb can stabilize recombinant Np9. Combined, these findings point to the possibility that Np9 affe...

Background In Xenopus retinogenesis, p27Xic1, a Xenopus cyclin dependent kinase inhibitor, functions as a cell fate determinant in both gliogenesis and neurogenesis in a context dependent manner. This activity is essential for co-ordination of determination and cell cycle regulation. However, very little is known about the mechanism regulating the context dependent choice between gliogenesis versus neurogenesis. Results We have identified NM23-X4, a NM23 family member, as a binding partner of p27Xic1. NM23-X4 is expressed at the periphery of the ciliary marginal zone of the Xenopus retina and the expression overlaps with p27Xic1 at the central side. Our in vivo functional analysis in Xenopus retina has shown that knockdown of NM23-X4 activates gliogenesis. Furthermore, co-overexpression of NM23-X4 with p27Xic1 results in the inhibition of p27Xic1-mediated gliogenesis, through direct interaction of NM23-X4 with the amino-terminal side of p27Xic1. This inhibitory effect on gliogenesis...

Embryonic stem cells represent an attractive source of cardiomyocytes for cell-replacement therapies. However, before embryonic stem cells can be successfully used for the treatment of cardiac diseases, the precise molecular mechanisms that underlie their cardiogenic differentiation must be identified. A network of intrinsic and extrinsic factors regulates embryonic stem cell self-renewal and differentiation into a variety of different cell lineages. Here, we show that Notch signaling takes place in some but not all embryonic stem cells and that the Notch pathway is shut down during the course of differentiation concomitantly with downregulation of Notch receptor and ligand expression. Moreover, gain- and loss-of-function experiments for Notch signaling components show that this pathway is a crucial regulator of cardiomyocyte differentiation within ES cells. Differentiation of ES cells into cardiomyocytes is favored by inactivation of the Notch1 receptor, whereas endogenous Notch si...