In mammals, the ventilatory response to decreased oxygen tension in the arterial blood is initiated by excitation of specialized O2-sensitive chemoreceptor cells in the carotid body that release neurotransmitters to activate endings of the sinus nerve afferent fibers. We investigated the role of ATP acting via ionotropic P2X receptors in the carotid body function and ventilatory response to hypoxia in mice. Mice deficient in P2X2 receptor subunit showed a markedly attenuated ventilatory response to hypoxia, whereas the response to hypoxia in P2X3-deficient mice was comparable with that seen in wild-type controls. P2X2 and P2X3 receptor subunit deficiency did not affect the ventilatory responses to hypercapnia. P2X2 subunit deficiency resulted in a dramatic reduction in the responses of the carotid sinus nerve to hypoxia in the in vitro carotid body-sinus nerve preparation. ATP and its stable analog alpha,beta-methyleneATP both evoked rapid excitation of sinus nerve afferents, and the P2 receptor antagonist PPADS (pyridoxal-5'-phosphate-6-azophenyl-2',4'-disulphonic acid) (100 microm) blocked hypoxia-induced increase in sinus nerve discharge. Immunoreactivities for P2X2 and P2X3 subunits were both detected on afferent terminals surrounding clusters of glomus cells in the wild-type animals but were absent in mice deficient in P2X2 and P2X3 receptor subunits. These observations provide the first definitive evidence that, in the carotid body, ATP is a key transmitter released by chemoreceptor cells to activate endings of the sinus nerve afferent fibers. We conclude that P2X receptors containing the P2X2 subunit play a pivotal role in carotid body function and in mediating ventilatory responses to hypoxia.
The regulation of inflammation is pivotal for preventing the development or reoccurrence of multiple sclerosis (MS). A biased ratio of high‐M1 versus low‐M2 polarized microglia is a major pathological feature of MS. Here, using microarray screening, we identify the long noncoding RNA (lncRNA) GAS5 as an epigenetic regulator of microglial polarization. Gain‐ and loss‐of‐function studies reveal that GAS5 suppresses microglial M2 polarization. Interference with GAS5 in transplanted microglia attenuates the progression of experimental autoimmune encephalomyelitis (EAE) and promotes remyelination in a lysolecithin‐induced demyelination model. In agreement, higher levels of GAS5 are found in amoeboid‐shaped microglia in MS patients. Further, functional studies demonstrate that GAS5 suppresses transcription of TRF4, a key factor controlling M2 macrophage polarization, by recruiting the polycomb repressive complex 2 (PRC2), thereby inhibiting M2 polarization. Thus, GAS5 may be a promising target for the treatment of demyelinating diseases.
The development of hippocampal circuitry depends on the proper assembly of correctly specified and fully differentiated hippocampal neurons. Little is known about factors that control the hippocampal specification. Here, we show that zinc finger protein Zbtb20 is essential for the specification of hippocampal CA1 field identity. We found that Zbtb20 expression was initially activated in the hippocampal anlage at the onset of corticogenesis, and persisted in immature hippocampal neurons. Targeted deletion of Zbtb20 in mice did not compromise the progenitor proliferation in the hippocampal and adjacent transitional ventricular zone, but led to the transformation of the hippocampal CA1 field into a transitional neocortex-like structure, as evidenced by cytoarchitectural, neuronal migration, and gene expression phenotypes. Correspondingly, the subiculum was ectopically located adjacent to the CA3 in mutant. Although the field identities of the mutant CA3 and dentate gyrus (DG) were largely maintained, their projections were severely impaired. The hippocampus of Zbtb20 null mice was reduced in size, and exhibited increased apoptotic cell death during postnatal development. Our data establish an essential role of Zbtb20 in the specification of CA1 field identity by repressing adjacent transitional neocortex-specific fate determination.cell fate | neocortex | zinc finger transcription factor
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