Persistent expression of helix-loop-helix factor HES-1 prevents mammalian neural differentiation in the central nervous system.

Ishibashi, Mākoto; Moriyoshi, Koki; Sasai, Yoshiki; Shiota, Kohei; Nakanishi, Shigetada; Kageyama, Ryoichiro

doi:10.1002/j.1460-2075.1994.tb06448.x

Cited by 371 publications

(265 citation statements)

References 29 publications

Supporting

Mentioning

242

Contrasting

Unclassified

Order By: Relevance

“…6). Previous reports have also observed that both overexpression of Hes1 and activated Notch signaling inhibits neuronal differentiation within the cortex (Ishibashi et al, 1994). We also found that the expanded progenitor zone observed in NICD Tg mice is coincident with expanded Sox2-immunopositive and nestin-immunopositive cells.…”

Section: Research Articlesupporting

confidence: 83%

Notch/Rbpjκ signaling regulates progenitor maintenance and differentiation of hypothalamic arcuate neurons

Aujla

Naratadam

et al. 2013

Development

View full text Add to dashboard Cite

SUMMARYThe hypothalamic arcuate nucleus (Arc), containing pro-opoiomelanocortin (POMC), neuropeptide Y (NPY) and growth hormone releasing hormone (GHRH) neurons, regulates feeding, energy balance and body size. Dysregulation of this homeostatic mediator underlies diseases ranging from growth failure to obesity. Despite considerable investigation regarding the function of Arc neurons, mechanisms governing their development remain unclear. Notch signaling factors such as Hes1 and Mash1 are present in hypothalamic progenitors that give rise to Arc neurons. However, how Notch signaling controls these progenitor populations is unknown. To elucidate the role of Notch signaling in Arc development, we analyzed conditional loss-of-function mice lacking a necessary Notch co-factor, Rbpjκ, in Nkx2.1-cre-expressing cells (Rbpjκ cKO), as well as mice with expression of the constitutively active Notch1 intracellular domain (NICD) in Nkx2.1-cre-expressing cells (NICD Tg). We found that loss of Rbpjκ results in absence of Hes1 but not of Hes5 within the primordial Arc at E13.5. Additionally, Mash1 expression is increased, coincident with increased proliferation and accumulation of Arc neurons at E13.5. At E18.5, Rbpjκ cKO mice have few progenitors and show increased numbers of differentiated Pomc, NPY and Ghrh neurons. By contrast, NICD Tg mice have increased hypothalamic progenitors, show an absence of differentiated Arc neurons and aberrant glial differentiation at E18.5. Subsequently, both Rbpjκ cKO and NICD Tg mice have changes in growth and body size during postnatal development. Taken together, our results demonstrate that Notch/Rbpjκ signaling regulates the generation and differentiation of Arc neurons, which contribute to homeostatic regulation of body size. KEY WORDS: Arcuate, Notch, POMC, NPY, Hypothalamus, MouseNotch/Rbpjκ signaling regulates progenitor maintenance and differentiation of hypothalamic arcuate neurons Paven K. Aujla, George T. Naratadam, Liwen Xu and Lori T. Raetzman* DEVELOPMENT 3512During embryonic development, cells migrate from the hypothalamic ventricular zone (HVZ) surrounding the ventral region of the third ventricle in order to form the Arc by E16.5 (Bayer and Altman, 1987;Ishii and Bouret, 2012;Shimada and Nakamura, 1973). One of the major functions of the Arc is to respond to food intake and energy expenditure. Energy-related hormone signals such as leptin are sensed by anorexic proopoiomelanocortin (POMC)/cocaine and amphetamine-regulated transcript (CART) neurons and orexic neuropeptide Y (NPY)/Agouti-related peptide (AgRP) neurons. POMC and NPY neurons regulate feeding behavior and are crucial to maintaining proper energy balance and homeostasis (Broberger, 2005;Morton et al., 2006;Srinivas et al., 2001). An additional subtype of neurons, growth hormone-releasing hormone (GHRH) neurons, are present in the Arc and regulate body size and growth by controlling release of growth hormone from the pituitary gland (Bouyer et al., 2007; Grossman et al., 1986).Despite the functional importance of ...

show abstract

Section: Research Articlesupporting

confidence: 83%

Notch/Rbpjκ signaling regulates progenitor maintenance and differentiation of hypothalamic arcuate neurons

Aujla

Naratadam

et al. 2013

Development

View full text Add to dashboard Cite

show abstract

“…Further confirmation of the immature character of the VZ cells was provided by analysis of HES-1 (Sasai et al, 1992) and Pax-6 expression. Overexpression of HES-1 in the rodent neural tube causes delay or inhibition of differentiation (Ishibashi et al, 1994), whereas HES-1 loss of function results in premature differentiation of neural plate precursor cells (Ishibashi et al, 1995). We observed that HES-1 expression was upregulated in the ventricular zone of Shh-Tg mice (Fig.…”

Section: Ectopic Shh Expression Confers Mixed Dorsal-ventral Charactementioning

confidence: 64%

Sonic hedgehogRegulates Proliferation and Inhibits Differentiation of CNS Precursor Cells

et al. 1999

View full text Add to dashboard Cite

Activation of the Sonic hedgehog (Shh) signal transduction pathway is essential for normal pattern formation and cellular differentiation in the developing CNS. However, it is also thought to be etiological in primitive neuroectodermal tumors. We adapted GAL4/UAS methodology to ectopically express full-length Shh in the dorsal neural tube of transgenic mouse embryos commencing at 10 d postcoitum (dpc), beyond the period of primary dorsal-ventral pattern formation and floorplate induction. Expression of Shh was maintained until birth, permitting us to investigate effects of ongoing exposure to Shh on CNS precursors in vivo. Proliferative rates of spinal cord precursors were twice that of wild-type littermates at 12.5 dpc. In contrast, at late fetal stages (18.5 dpc), cells that were Shh-responsive but postmitotic were present in persistent structures reminiscent of the ventricular zone germinal matrix. This tissue remained blocked in an undifferentiated state. These results indicate that cellular competence restricts the proliferative response to Shh in vivo and provide evidence that proliferation and differentiation can be regulated separately in precursor cells of the spinal cord. Thus, Hedgehog signaling may contribute to CNS tumorigenesis by directly enhancing proliferation and preventing neural differentiation in selected precursor cells.

show abstract

“…When RBP-Jbinding sites in the Hes1 promoter were disrupted, the complex cannot interact with the promoter and Hes1 upregulation was completely abolished (Fig 2, Hes1/RBP-J(-)). Since Hes1 and Hes5 are known to inhibit neuronal differentiation [10], the above data suggest that the two Hes genes may mediate Notch-induced inhibition of cellular differentiation.…”

Section: The Notch Pathway: Cleavage and Translocation Of Notchmentioning

confidence: 82%

The Notch-Hes pathway in mammalian neural development

1999

View full text Add to dashboard Cite

A wide variety of neurons and glial cells differentiate from common precursor cells in the developing nervous system. During this process, Notch-mediated cell-cell interaction is essential for maintenance of dividing cells and subsequent generation of cell type diversity. Activation of Notch inhibits cellular differentiation, and abnormality of the Notch pathway leads to premature neuronal differentiation, the lack of some cell types, and severe defects of tissue morphogenesis. Recent data demonstrate that Notch fails to inhibit cellular differentiation in the absence of the bHLH genes Hes1 and Hes5, which functionally antagonize the neuronal bHLH genes such as Mash1. These results indicate that the two Hes genes are essential effectors for the Notch pathway and that neuronal differentiation is controlled by the pathway "Notch-Hes1/ Hes5-|Mash1".

show abstract

Persistent expression of helix-loop-helix factor HES-1 prevents mammalian neural differentiation in the central nervous system.

Cited by 371 publications

References 29 publications

Notch/Rbpjκ signaling regulates progenitor maintenance and differentiation of hypothalamic arcuate neurons

Notch/Rbpjκ signaling regulates progenitor maintenance and differentiation of hypothalamic arcuate neurons

Sonic hedgehogRegulates Proliferation and Inhibits Differentiation of CNS Precursor Cells

The Notch-Hes pathway in mammalian neural development

Contact Info

Product

Resources

About