Neural precursor differentiation into astrocytes requires signaling through the leukemia inhibitory factor receptor

Koblar, Simon; Turnley, Ann M.; Classon, Brendan J.; Reid, K L; Ware, Carol B.; Cheema, Surindar S.; Murphy, Mark; Bartlett, Perry F.

doi:10.1073/pnas.95.6.3178

Cited by 187 publications

(142 citation statements)

References 21 publications

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“…Hippocampal cell cultures prepared from LIF −/− mice had significantly fewer GFAP + astrocytes (12 ± 1%, n = 10) compared with wt mice (17 ± 2%, n = 8) (P < 0.05) consistent with the in vivo findings (Bugga et al, 1998;Koblar et al, 1998). There were no significant effects on either neuronal cell numbers or OPC cell numbers in LIF −/− mice.…”

Section: Lif Is Required For Development Of Hippocampal Gliasupporting

confidence: 79%

Activity-dependent neuron–glial signaling by ATP and leukemia-inhibitory factor promotes hippocampal glial cell development

Cohen

Fields

2008

Neuron Glia Biol.

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Activity-dependent signaling between neurons and astrocytes contributes to experience-dependent plasticity and development of the nervous system. However, mechanisms responsible for neuronglial interactions and the releasable factors that underlie these processes are not well understood. The pro-inflammatory cytokine, leukemia-inhibitory factor (LIF), is transiently expressed postnatally by glial cells in the hippocampus and rapidly up-regulated by enhanced neural activity following seizures. To test the hypothesis that spontaneous neural activity regulates glial development in hippocampus via LIF signaling, we blocked spontaneous activity with the sodium channel blocker tetrodotoxin (TTX) in mixed hippocampal cell cultures in combination with blockers of LIF and purinergic signaling. TTX decreased the number of GFAP-expressing astrocytes in hippocampal cell culture. Furthermore, blocking purinergic signaling by P2Y receptors contributed to reduced numbers of astrocytes. Blocking activity or purinergic signaling in the presence of function-blocking antibodies to LIF did not further decrease the number of astrocytes. Moreover, hippocampal cell cultures prepared from LIF −/− mice had reduced numbers of astrocytes and activity-dependent neuron-glial signaling promoting differentiation of astrocytes was absent. The results show that endogenous LIF is required for normal development of hippocampal astrocytes, and this process is regulated by spontaneous neural impulse activity through the release of ATP.

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Section: Lif Is Required For Development Of Hippocampal Gliasupporting

confidence: 79%

Activity-dependent neuron–glial signaling by ATP and leukemia-inhibitory factor promotes hippocampal glial cell development

Cohen

Fields

2008

Neuron Glia Biol.

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“…5d,e). Moreover, the importance of this LIF-triggered Jak-STAT pathway in astrocyte differentiation in vivo has been further substantiated by knockout studies [25][26][27] ( Supplementary Fig. 1), placing this pathway at the center of the astrogliogenic machinery.…”

Section: A Positive Autoregulatory Loop Of the Jak-stat Machinerymentioning

confidence: 88%

“…Previous loss-of-function studies (for instance, gene knockout experiments knocking out ligands, receptors, or signaling molecules) have demonstrated the importance of Jak-STAT signaling in glial differentiation in vivo [25][26][27] (Supplementary Fig. 1).…”

Section: Discussionmentioning

confidence: 98%

“…This autoregulatory loop coordinates different parts of the pathway to synchronize the elevation or suppression of Jak-STAT signaling. Although our data demonstrate a transcriptional activation mechanism, it is likely that post-transcriptional mechanisms could also be a part of the autoregulatory loop.Previous loss-of-function studies (for instance, gene knockout experiments knocking out ligands, receptors, or signaling molecules) have demonstrated the importance of Jak-STAT signaling in glial differentiation in vivo [25][26][27] (Supplementary Fig. 1).…”

mentioning

confidence: 98%

“…Mouse knockout studies have demonstrated that genetic deficiency in major components of this pathway, including LIF, its receptors LIFRβ and gp130, or the signaling molecules STAT1/3, leads to impaired astroglial differentiation [25][26][27] ( Supplementary Fig. 1).…”

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confidence: 99%

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A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis

et al. 2005

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During development of the CNS, neurons and glia are generated in a sequential manner. The mechanism underlying the later onset of gliogenesis is poorly understood, although the cytokineinduced Jak-STAT pathway has been postulated to regulate astrogliogenesis. Here, we report that the overall activity of Jak-STAT signaling is dynamically regulated in mouse cortical germinal zone during development. As such, activated STAT1/3 and STAT-mediated transcription are negligible at early, neurogenic stages, when neurogenic factors are highly expressed. At later, gliogenic periods, decreased expression of neurogenic factors causes robust elevation of STAT activity. Our data demonstrate a positive autoregulatory loop whereby STAT1/3 directly induces the expression of various components of the Jak-STAT pathway to strengthen STAT signaling and trigger astrogliogenesis. Forced activation of Jak-STAT signaling leads to precocious astrogliogenesis, and inhibition of this pathway blocks astrocyte differentiation. These observations suggest that autoregulation of the Jak-STAT pathway controls the onset of astrogliogenesis.During embryonic development, the generation of three major neural cell types (neurons, astrocytes, and oligodendrocytes) in the CNS occurs sequentially, whereby almost all neurons are generated before the appearance of glial cells 1,2 , with the exception of a few COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. NIH Public Access Author ManuscriptNat Neurosci. Author manuscript; available in PMC 2014 November 06. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript sites of postnatal and adult neurogenesis such as the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ) of the forebrain 3 . This strategy of building the CNS through sequential production of neurons and glia has become more comprehensible, as recent findings have demonstrated that glial cells are important in critical neuronal maturation processes such as axonal path finding and synapse formation [4][5][6] . It is conceivable that delayed or precocious production of glial cells may lead to inappropriate wiring, disorganization, and eventually, dysfunction of the CNS.The 'neurons-first, glia-second' differentiation theme for neural progenitors can be recapitulated in culture. Cortical neural progenitor stem cells isolated from relatively early embryonic stages (for example, mouse embryonic day (E) 10-11) give rise to neurons, not glial cells, after short-term culturing (fewer than 4 d), whereas cortical progenitors isolated from perinatal stages tend to differentiate into astrocytes under the same culture conditions 7 .In addition, both E10-11 cortical progenitors and embryonic stem cell-derived neural stem or progenitor cells (NSCs or NPCs) switch from being neurogenic to gliogenic over time in vitro 8,9 , suggesting that the molecular switch for the transition from neurogenesis to gliogenesis may be internally programmed in neural progenitors.S...

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Developmental changes in progenitor cell responsiveness to cytokines

et al. 1999

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Multipotent progenitor cells have been identified within periventricular generative zones of the developing and adult brain. To determine whether the environmental responsiveness of these cells changes during development, progenitor cells were cultured from embryonic, postnatal, and adult rat brain in the presence of either basic fibroblast growth factor (bFGF) or epidermal growth factor (EGF). Embryonic cells cultured as intact progenitor neurospheres proliferated more robustly in response to bFGF than to EGF, whereas proliferation of postnatal and adult progenitor cells was enhanced more by EGF than bFGF. Progenitor cells generated in the presence of either bFGF or EGF had the capacity to generate neurons, astrocytes, and oligodendrocytes at all developmental stages. Most embryonic and neonatal bFGF-generated cells differentiated predominantly into neurons, whereas late stage embryonic and neonatal EGF-generated progenitors largely remained in an undifferentiated state. However, later postnatal and adult progenitor species, irrespective of whether they were generated in the presence of bFGF or EGF, gave rise preferentially to astrocytes. Treatment with bone morphogenetic protein (BMP)2 or BMP7 enhanced astroglial differentiation and suppressed oligodendroglial differentiation of both EGF- and bFGF-generated progenitor species, suggesting that the effects of the BMPs are not dependent on EGF receptor activation. Thus, while central nervous system (CNS) progenitor cells retain multipotent capacity and responsiveness to the BMPs throughout development, they exhibit significant changes in other cellular response properties, perhaps reflecting differences in the requirements for specific generative versus regenerative events.

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Neural precursor differentiation into astrocytes requires signaling through the leukemia inhibitory factor receptor

Cited by 187 publications

References 21 publications

Activity-dependent neuron–glial signaling by ATP and leukemia-inhibitory factor promotes hippocampal glial cell development

Activity-dependent neuron–glial signaling by ATP and leukemia-inhibitory factor promotes hippocampal glial cell development

A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis

Developmental changes in progenitor cell responsiveness to cytokines

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