Progenitors resume generating neurons after temporary inhibition of neurogenesis by Notch activation in the mammalian cerebral cortex

Mizutani, Ken-ichi; Saito, Tetsuichiro

doi:10.1242/dev.01693

Cited by 114 publications

(91 citation statements)

References 48 publications

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“…Loss of Hes1 and Hes5 result in progenitor depletion and promote premature neuronal differentiation (Kageyama et al, 2005;Yoon and Gaiano, 2005). By contrast, increased or persistent activation of Notch1 promotes maintenance of a progenitor state and inhibits neuronal differentiation (Gaiano et al, 2000;Mizutani and Saito, 2005). Taken together with reports of Hes1 and Hes5 in the developing Arc (Kita et al, 2007;McNay et al, 2006;Pelling et al, 2011;Shimogori et al, 2010), we hypothesize that Notch/Rbpjκ signaling may play a role in maintaining progenitors and controlling differentiation of Arc neurons.…”

Section: Introductionmentioning

confidence: 58%

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: 58%

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

Aujla

Naratadam

et al. 2013

Development

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“…Furthermore, this aspect of Notch activity may be a general feature of nervous system development. Sustaining Notch activity for a period and then releasing it in the cerebral cortex allowed resumption of the production of the temporally appropriate neurons (33). Similarly, the well defined progenitor progression which occurs in the Drosophila CNS does not depend on the precise regulation of Notch activity (34).…”

Section: Discussionmentioning

confidence: 99%

Notch activity permits retinal cells to progress through multiple progenitor states and acquire a stem cell property

Jadhav

Cho

Cepko

2006

Proc. Natl. Acad. Sci. U.S.A.

158

147

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Signaling through the Notch pathway regulates multiple aspects of development. The vertebrate retina allows an investigation of the basis for these various effects, because the major cell types of the retina arise from a common progenitor that expresses Notch1 . The Notch pathway was constitutively activated in distinct populations of retinal cells during development. Prolonged Notch activity in progenitor cells maintained cells in the progenitor state without perturbing temporal identity, promoting early progenitor characteristics early in development and late progenitor characteristics later in development. Eventually, constitutive Notch activation led these cells to acquire characteristics of glial and stem cells. In contrast, reactivating the Notch pathway in newly postmitotic retinal cells promoted mature glial cell formation in a subset of cells. These data suggest that prolonged Notch activity does not disrupt the normal progression of progenitor temporal states, and that down-regulating or overcoming Notch activity is required for proper formation of both neuronal and glial cell fates.

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“…BrdU incorporation was then assessed in the adult offspring. This BrdU concentration is sufficient to label rapidly dividing embryonic neural progenitor cells in vivo with a single injection (Mizutani and Saito, 2005). The morning of detection of postcopulatory vaginal plug was considered E0.5.…”

Section: Brdu Injectionsmentioning

confidence: 99%

Anatomical location of mature GnRH neurons corresponds with their birthdate in the developing mouse

Jasoni

Porteous

Herbison

2009

Developmental Dynamics

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The gonadotropin-releasing hormone (GnRH) neurons exhibit substantial functional, anatomical, and molecular heterogeneity, which has hampered their thorough examination. This study was undertaken in an effort to understand whether the anatomical distribution of GnRH neurons is related to their developmental history, because such an association may help explain differences within the population. Using bromodeoxyuridine pulse labeling of timed pregnant female mice we labeled dividing cells, including GnRH neuron progenitors in the olfactory placode, throughout the window of GnRH neuron differentiation. Our results indicate that cells that become postmitotic early tend to populate the rostral aspects of the adult GnRH neuron continuum, whereas later-generated cells tend to settle more caudally; an inside-out pattern reminiscent of neocortex. These observations suggest that the timing of differentiation influences the ability of postmitotic GnRH neurons to navigate to their adult location, and hence may be important in determining the ultimate wiring of the adult network. Developmental Dynamics 238:524 -531, 2009.

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Progenitors resume generating neurons after temporary inhibition of neurogenesis by Notch activation in the mammalian cerebral cortex

Cited by 114 publications

References 48 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

Notch activity permits retinal cells to progress through multiple progenitor states and acquire a stem cell property

Anatomical location of mature GnRH neurons corresponds with their birthdate in the developing mouse

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