Sonic Hedgehog regulates Hes1 through a novel mechanism that is independent of canonical Notch pathway signalling

Ingram, Wendy J.; McCue, Karen; Tran, Thomas-Toan; Hallahan, Andrew R.; Wainwright, Brandon

doi:10.1038/sj.onc.1210767

Cited by 147 publications

(111 citation statements)

References 59 publications

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“…Within the nucleus, the NICD/Rbpjκ/MAM induces transcription of basic helix-loop-helix (bHLH) transcription factors encoded by Hes and Hey genes (Iso et al, 2003). Adding complexity to the system, Notch can signal independently of Rbpjκ/MAM, and Hes genes induced by signals other than Notch/Rbpjκ and Rbpjκ/MAM can also have transcriptional activity independently of Notch (Brennan and Gardner, 2002;Ingram et al, 2008;Johnson and Macdonald, 2011;Martinez Arias et al, 2002;Wall et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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

Aujla

Naratadam

et al. 2013

Development

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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 ...

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Section: Introductionmentioning

confidence: 99%

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

Aujla

Naratadam

et al. 2013

Development

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“…84 Hes1 inhibition which is conducted by cyclopamine incubation indicates that Hes1 expression involves canonical Hedgehog signaling, because cyclopamine blocks Hedgehog downstream factor Smo function. 85 In the retina progenitor cells, Hedgehog signaling activates Hes1 expression in the presence of GSI, as Hedgehog downstream factor Gli2 directly binds to Hes1 promoter and accelerate Hes1 level without activating CSL. 86 The requirement of Gli2 in Hes1 regulation is also observed in telencephalic neuroepithelial stem cells.…”

Section: Canonical Notch Signaling Pathwaymentioning

confidence: 99%

Hes1: a key role in stemness, metastasis and multidrug resistance

Liu¹,

Dai²,

Du³

2015

Cancer Biology & Therapy

159

116

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“…Further investigation of the expression of Notch and Hedgehog pathway targets revealed that expression of the canonical Notchsignaling target gene Hes5 is lost from the EGL at E18.5 in the absence of RBP-J as expected (Figures 3a and c) and is not restored after Hedgehog pathway activation (Figure 3d). The Hes1 gene is a context-dependent target gene of both the Notch and Hedgehog-signaling pathways (Ingram et al, 2008;Wall and Wallace, 2009) and is expressed at a low level in the E18.5 EGL of both control and RBP-J lox/lox ;GFAP-Cre mice (Figures 3e and g), but is significantly upregulated after Hedgehog pathway activation in both Ptc1 lox/lox ;GFAP-Cre and Ptc1 lox/lox ;RBP-J lox/lox ;GFAP-Cre mice (Figures 3f and h). ;RBP-J lox/lox ;GFAP-Cre EGL (m-p).…”

Section: Loss Of Notch Signaling In Gfapmentioning

confidence: 99%

Canonical Notch signaling is not required for the growth of Hedgehog pathway-induced medulloblastoma

et al. 2010

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Sonic Hedgehog regulates Hes1 through a novel mechanism that is independent of canonical Notch pathway signalling

Cited by 147 publications

References 59 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

Hes1: a key role in stemness, metastasis and multidrug resistance

Canonical Notch signaling is not required for the growth of Hedgehog pathway-induced medulloblastoma

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