Biomedical subjects

Dalia Goldenberg

Publications and source records attributed to Dalia Goldenberg.

5 recordsLinked to original sources

PubMed2006

Runx3 regulates dendritic epidermal T cell development.

The Runx3 transcription factor regulates development of T cells during thymopoiesis and TrkC sensory neurons during dorsal root ganglia neurogenesis. It also mediates transforming growth factor-beta signaling in dendritic cells and is essential for development of skin Langerhans cells. Here, we report that Runx3 is involved in the development of skin dendritic epidermal T cells (DETCs); an important component of tissue immunoregulation. In developing DETCs, Runx3 regulates expression of the alphaEbeta7 integrin CD103, known to affect migration and epithelial retention of DETCs. It also regulates expression of IL-2 receptor beta (IL-2Rbeta) that mediates cell proliferation in response to IL-2 or IL-15. In the absence of Runx3, the reduction in CD103 and IL-2Rbeta expression on Runx3(-/-) DETC precursors resulted in impaired cell proliferation and maturation, leading to complete lack of skin DETCs in Runx3(-/-) mice. The data demonstrate the requirement of Runx3 for DETCs development and underscore the importance of CD103 and IL-2Rbeta in this process. Of note, while Runx3(-/-) mice lack both DETCs and Langerhans cells, the two most important components of skin immune surveillance, the mice did not develop skin lesions under pathogen-free (SPF) conditions.

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PubMed2004

Runx3 regulates mouse TGF-beta-mediated dendritic cell function and its absence results in airway inflammation.

Runx3 transcription factor regulates cell lineage decisions in thymopoiesis and neurogenesis. Here we report that Runx3 knockout (KO) mice develop spontaneous eosinophilic lung inflammation associated with airway remodeling and mucus hypersecretion. Runx3 is specifically expressed in mature dendritic cells (DC) and mediates their response to TGF-beta. In the absence of Runx3, DC become insensitive to TGF-beta-induced maturation inhibition, and TGF-beta-dependent Langerhans cell development is impaired. Maturation of Runx3 KO DC is accelerated and accompanied by increased efficacy to stimulate T cells and aberrant expression of beta2-integrins. Lung alveoli of Runx3 KO mice accumulate DC characteristic of allergic airway inflammation. Taken together, abnormalities in DC function and subset distribution may constitute the primary immune system defect, which leads to the eosinophilic lung inflammation in Runx3 KO mice. These data may help elucidate the molecular mechanisms underlying the pathogenesis of allergic airway inflammation in humans.

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PubMed2003

Runx3 and Runx1 are required for CD8 T cell development during thymopoiesis.

The RUNX transcription factors are important regulators of lineage-specific gene expression. RUNX are bifunctional, acting both as activators and repressors of tissue-specific target genes. Recently, we have demonstrated that Runx3 is a neurogenic transcription factor, which regulates development and survival of proprioceptive neurons in dorsal root ganglia. Here we report that Runx3 and Runx1 are highly expressed in thymic medulla and cortex, respectively, and function in development of CD8 T cells during thymopoiesis. Runx3-deficient (Runx3 KO) mice display abnormalities in CD4 expression during lineage decisions and impairment of CD8 T cell maturation in the thymus. A large proportion of Runx3 KO peripheral CD8 T cells also expressed CD4, and in contrast to wild-type, their proliferation ability was largely reduced. In addition, the in vitro cytotoxic activity of alloimmunized peritoneal exudate lymphocytes was significantly lower in Runx3 KO compared with WT mice. In a compound mutant mouse, null for Runx3 and heterozygous for Runx1 (Runx3-/-;Runx1+/-), all peripheral CD8 T cells also expressed CD4, resulting in a complete lack of single-positive CD8+ T cells in the spleen. The results provide information on the role of Runx3 and Runx1 in thymopoiesis and suggest that both act as transcriptional repressors of CD4 expression during T cell lineage decisions.

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PubMed2002

The Runx3 transcription factor regulates development and survival of TrkC dorsal root ganglia neurons.

The RUNX transcription factors are important regulators of linage-specific gene expression in major developmental pathways. Recently, we demonstrated that Runx3 is highly expressed in developing cranial and dorsal root ganglia (DRGs). Here we report that within the DRGs, Runx3 is specifically expressed in a subset of neurons, the tyrosine kinase receptor C (TrkC) proprioceptive neurons. We show that Runx3-deficient mice develop severe limb ataxia due to disruption of monosynaptic connectivity between intra spinal afferents and motoneurons. We demonstrate that the underlying cause of the defect is a loss of DRG proprioceptive neurons, reflected by a decreased number of TrkC-, parvalbumin- and beta-galactosidase-positive cells. Thus, Runx3 is a neurogenic TrkC neuron-specific transcription factor. In its absence, TrkC neurons in the DRG do not survive long enough to extend their axons toward target cells, resulting in lack of connectivity and ataxia. The data provide new genetic insights into the neurogenesis of DRGs and may help elucidate the molecular mechanisms underlying somatosensory-related ataxia in humans.

Afferent Pathways↗

PubMedDate not supplied

Phylogenesis and regulated expression of the RUNT domain transcription factors RUNX1 and RUNX3.

The RUNX transcription factors are key regulators of lineage specific gene expression in developmental pathways. The mammalian RUNX genes arose early in evolution and maintained extensive structural similarities. Sequence analysis suggested that RUNX3 is the most ancient of the three mammalian genes, consistent with its role in neurogenesis of the monosynaptic reflex arc, the simplest neuronal response circuit, found in Cnidarians, the most primitive animals. All RUNX proteins bind to the same DNA motif and act as activators or repressors of transcription through recruitment of common transcriptional modulators. Nevertheless, analysis of Runx1 and Runx3 expression during embryogenesis revealed that their function is not redundant. In adults both Runx1 and Runx3 are highly expressed in the hematopoietic system. At early embryonic stages we found strong Runx3 expression in dorsal root ganglia neurons, confined to TrkC sensory neurons. In the absence of Runx3, knockout mice develop severe ataxia due to the early death of the TrkC neurons. Other phenotypic defects of Runx3 KO mice including abnormalities in thymopoiesis are also being investigated.

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