Persistent expression of activated notch in the developing hypothalamus affects survival of pituitary progenitors and alters pituitary structure

Aujla, Paven K.; Bogdanovic, Vedran; Naratadam, George T.; Raetzman, Lori T.

doi:10.1002/dvdy.24283

Cited by 15 publications

(9 citation statements)

References 71 publications

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“…We performed in situ hybridization as previously-described (Biehl and Raetzman, 2015; Aujla et al, 2015). Samples were fixed in paraformaldehyde (4% w/v in 1× PBS) for 10 min, permeabilized with 0.3% Triton X-100 in 1× PBS for 15 min, and digested with Proteinase K (0.1 µg/ml) for 15 min at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Spatial patterning of liver progenitor cell differentiation mediated by cellular contractility and Notch signaling

Kaylan

Berg

Biehl

et al. 2018

eLife

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The progenitor cells of the developing liver can differentiate toward both hepatocyte and biliary cell fates. In addition to the established roles of TGFβ and Notch signaling in this fate specification process, there is increasing evidence that liver progenitors are sensitive to mechanical cues. Here, we utilized microarrayed patterns to provide a controlled biochemical and biomechanical microenvironment for mouse liver progenitor cell differentiation. In these defined circular geometries, we observed biliary differentiation at the periphery and hepatocytic differentiation in the center. Parallel measurements obtained by traction force microscopy showed substantial stresses at the periphery, coincident with maximal biliary differentiation. We investigated the impact of downstream signaling, showing that peripheral biliary differentiation is dependent not only on Notch and TGFβ but also E-cadherin, myosin-mediated cell contractility, and ERK. We have therefore identified distinct combinations of microenvironmental cues which guide fate specification of mouse liver progenitors toward both hepatocyte and biliary fates.

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Section: Methodsmentioning

confidence: 99%

Spatial patterning of liver progenitor cell differentiation mediated by cellular contractility and Notch signaling

Kaylan

Berg

Biehl

et al. 2018

eLife

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“…In situ hybridization was also performed as previously described by our lab (Aujla, et al 2015). Briefly, slides were deparaffinized, washed, permeabilized, digested with Proteinase-K, acetylated, and incubated in hybridization solution (at 64° C for Pomc or 55° C for Kiss1).…”

Section: Methodsmentioning

confidence: 99%

Rbpj-κ mediated Notch signaling plays a critical role in development of hypothalamic Kisspeptin neurons

Biehl

Raetzman

2015

Developmental Biology

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The mammalian arcuate nucleus (ARC) houses neurons critical for energy homeostasis and sexual maturation. Proopiomelanocortin (POMC) and Neuropeptide Y (NPY) neurons function to balance energy intake and Kisspeptin neurons are critical for the onset of puberty and reproductive function. While the physiological roles of these neurons have been well established, their development remains unclear. We have previously shown that Notch signaling plays an important role in cell fate within the ARC of mice. Active Notch signaling prevented neural progenitors from differentiating into feeding circuit neurons, whereas conditional loss of Notch signaling lead to a premature differentiation of these neurons. Presently, we hypothesized that Kisspeptin neurons would similarly be affected by Notch manipulation. To address this, we utilized mice with a conditional deletion of the Notch signaling co-factor Rbpj-κ (Rbpj cKO), or mice persistently expressing the Notch1 intracellular domain (NICD tg) within Nkx2.1 expressing cells of the developing hypothalamus. Interestingly, we found that in both models, a lack of Kisspeptin neurons are observed. This suggests that Notch signaling must be properly titrated for formation of Kisspeptin neurons. These results led us to hypothesize that Kisspeptin neurons of the ARC may arise from a different lineage of intermediate progenitors than NPY neurons and that Notch was responsible for the fate choice between these neurons. To determine if Kisspeptin neurons of the ARC differentiate similarly through a Pomc intermediate, we utilized a genetic model expressing the tdTomato fluorescent protein in all cells that have ever expressed Pomc. We observed some Kisspeptin expressing neurons labeled with the Pomc reporter similar to NPY neurons, suggesting that these distinct neurons can arise from a common progenitor. Finally, we hypothesized that temporal differences leading to premature depletion of progenitors in cKO mice lead to our observed phenotype. Using a BrdU birthdating paradigm, we determined the percentage of NPY and Kisspeptin neurons born on embryonic days 11.5, 12.5, and 13.5. We found no difference in the timing of differentiation of either neuronal subtype, with a majority occurring at e11.5. Taken together, our findings suggest that active Notch signaling is an important molecular switch involved in instructing subpopulations of progenitor cells to differentiate into Kisspeptin neurons.

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“…The separation between head mesenchyme of neural crest and definitive mesoderm origins on either side of the pituitary gland presents intriguing possibilities for differential effects of these mesenchymal populations on pituitary gland organogenesis. For instance, stimulation of Notch signaling in the ventral diencephalon reduces Fgf10 expression in the pituitary organizer, which reduces Lhx3 expression in Rathke’s pouch and increases apoptosis [ 52 ]. Lhx3 expression is reduced preferentially on the caudal side of Rathke’s pouch and apoptosis is preferentially increased [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

“…For instance, stimulation of Notch signaling in the ventral diencephalon reduces Fgf10 expression in the pituitary organizer, which reduces Lhx3 expression in Rathke’s pouch and increases apoptosis [ 52 ]. Lhx3 expression is reduced preferentially on the caudal side of Rathke’s pouch and apoptosis is preferentially increased [ 52 ]. The differential effects on Rathke’s pouch may be caused by signals from the definitive mesoderm, which are not expressed in the neural crest derived mesoderm.…”

Section: Discussionmentioning

confidence: 99%

β-catenin is required in the neural crest and mesencephalon for pituitary gland organogenesis

et al. 2016

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BackgroundThe pituitary gland is a highly vascularized tissue that requires coordinated interactions between the neural ectoderm, oral ectoderm, and head mesenchyme during development for proper physiological function. The interactions between the neural ectoderm and oral ectoderm, especially the role of the pituitary organizer in shaping the pituitary precursor, Rathke’s pouch, are well described. However, less is known about the role of head mesenchyme in pituitary organogenesis. The head mesenchyme is derived from definitive mesoderm and neural crest, but the relative contributions of these tissues to the mesenchyme adjacent to the pituitary are not known.ResultsWe carried out lineage tracing experiments using two neural crest-specific mouse cre lines, Wnt1-cre and P0-cre, and determined that the head mesenchyme rostral to the pituitary gland is neural crest derived. To assess the role of the neural crest in pituitary development we ablated it, using Wnt1-cre to delete Ctnnb1 (β-catenin), which is required for neural crest development. The Wnt1-cre is active in the neural ectoderm, principally in the mesencephalon, but also in the posterior diencephalon. Loss of β-catenin in this domain causes a rostral shift in the ventral diencephalon, including the pituitary organizer, resulting in pituitary dysmorphology. The neural crest deficient embryos have abnormally dilated pituitary vasculature due to a loss of neural crest derived pericytes.Conclusionsβ-catenin in the Wnt1 expression domain, including the neural crest, plays a critical role in regulation of pituitary gland growth, development, and vascularization.Electronic supplementary materialThe online version of this article (doi:10.1186/s12861-016-0118-9) contains supplementary material, which is available to authorized users.

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Persistent expression of activated notch in the developing hypothalamus affects survival of pituitary progenitors and alters pituitary structure

Cited by 15 publications

References 71 publications

Spatial patterning of liver progenitor cell differentiation mediated by cellular contractility and Notch signaling

Spatial patterning of liver progenitor cell differentiation mediated by cellular contractility and Notch signaling

Rbpj-κ mediated Notch signaling plays a critical role in development of hypothalamic Kisspeptin neurons

β-catenin is required in the neural crest and mesencephalon for pituitary gland organogenesis

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