p63 Regulates Olfactory Stem Cell Self-Renewal and Differentiation

Fletcher, Russell B.; Prasol, Melanie S.; Estrada, José L.; Baudhuin, Ariane; Vranizan, Karen; Choi, Yoon Gi; Ngai, John

doi:10.1016/j.neuron.2011.09.009

Cited by 113 publications

(153 citation statements)

References 57 publications

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“…How do these data reconcile with previous reports showing that the prostate luminal cell compartment can form and expand in the complete absence of ΔNp63-positive cells? In other tissues, p63 (and specifically ΔNp63) is required to maintain progenitor/stem cells but is dispensable for cell differentiation (19)(20)(21)(22)(23)(24). For instance, the epidermis of p63 −/− embryos at 17 dpc contains clusters of cells expressing the differentiation markers loricrin, filaggrin, and involucrin, indicating that p63-null ectoderm can produce differentiated epidermal cells in the absence of functional progenitors (19,27).…”

Section: Discussionmentioning

confidence: 99%

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p63-expressing cells are the stem cells of developing prostate, bladder, and colorectal epithelia

Pignon

Grisanzio

Geng

et al. 2013

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

189

194

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The tumor protein p63 (p63), and more specifically the NH2-terminal truncated (ΔN) p63 isoform, is a marker of basal epithelial cells and is required for normal development of several epithelial tissues, including the bladder and prostate glands. Although p63-expressing cells are proposed to be the stem cells of the developing prostate epithelium and bladder urothelium, cell lineages in these endoderm-derived epithelia remain highly controversial, and rigorous lineage tracing studies are warranted. Here, we generated knock-in mice expressing Cre recombinase (Cre) under the control of the endogenous ΔNp63 promoter. Heterozygote ΔNp63 +/Cre mice were phenotypically normal and fertile. Cremediated recombination in ΔNp63 +/Cre ;ROSA26 EYFP reporter mice faithfully recapitulated the pattern of ΔNp63 expression and were useful for genetic lineage tracing of ΔNp63-expressing cells of the caudal endoderm in vivo. We found that ΔNp63-positive cells of the urogenital sinus generated all epithelial lineages of the prostate and bladder, indicating that these cells represent the stem/ progenitor cells of those epithelia during development. We also observed ΔNp63 expression in caudal gut endoderm and the contribution of ΔNp63-positive cells to the stem/progenitor compartment of adult colorectal epithelium. Because p63 is a master regulator of stratified epithelial development, this finding provides a unique developmental insight into the cell of origin of squamous cell metaplasia and squamous cell carcinoma of the colon.large intestine | hindgut | genitourinary tract

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Section: Discussionmentioning

confidence: 99%

“…Specific KO mice for the TA and the ΔNp63 isoforms reveal that these anomalies result from ΔNp63 absence (18,19). Phenotypes in p63 KO or mutant mice result, among other reasons, from apparent defects in stem and progenitors cells' capacity to proliferate or survive (19)(20)(21)(22)(23)(24).…”

mentioning

confidence: 99%

p63-expressing cells are the stem cells of developing prostate, bladder, and colorectal epithelia

Pignon

Grisanzio

Geng

et al. 2013

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

189

194

View full text Add to dashboard Cite

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“…HBCs express the transcription factor p63, which is essential for the proliferation of epithelial stem cells that give rise to the thymus and epidermis [12]. Recently, two interesting studies clarified the role of p63 in the regulation of HBC's cellular dynamics [13,14]; however, despite these and other studies, the detailed mechanisms that underlie HBC differentiation and proliferation remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Horizontal Basal Cell-Specific Deletion ofPax6Impedes Recovery of the Olfactory Neuroepithelium Following Severe Injury

Suzuki

Sakurai

Yamazaki

et al. 2015

Stem Cells and Development

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In the mammalian olfactory epithelium (OE), olfactory receptor neurons (ORNs) are continuously regenerated throughout the animal's lifetime. Horizontal basal cells (HBCs) in the OE express the epithelial marker keratin 5 (K5) and the stem cell marker Pax6 and are considered relatively quiescent tissue stem cells in the OE. Pax6 is a key regulator of several developmental processes in the central nervous system and in sensory organs. Although Pax6 is expressed in the OE, its precise role remains unknown, particularly with respect to stem celllike HBCs. To investigate the function of Pax6 in the developmental and regenerative processes in the OE, we generated conditional Pax6-knockout mice carrying a loxP-floxed Pax6 gene. Homozygous Pax6-floxed mice were crossed with K5-Cre transgenic mice to generate HBC-specific Pax6-knockout (Pax6-cKO) mice. We confirmed that the deletion of Pax6 expression in HBCs was sufficiently achieved in zone 1 of the OE in Pax6-cKO mice 3 days after methimazole-induced severe damage. In this condition, regeneration of the OE was dramatically impaired; both OE thickness and the number of ORNs were significantly decreased in the regenerated OE of Pax6-cKO mice. These results suggest that Pax6 expression is essential for HBCs to differentiate into neuronal cells during the regeneration process following severe injury.

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“…As in other selfrenewing tissues, it is the presence of stem and progenitor cells that underlie the regenerative capacity. OE basal layers contain a heterogeneous progenitor population (Goldstein and Schwob, 1996;Goldstein et al, 1998;Chen et al, 2004;Leung et al, 2007;Fletcher et al, 2011), and the niche signals regulating renewal and differentiation remain incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

Adult c‐Kit(+) progenitor cells are necessary for maintenance and regeneration of olfactory neurons

Goldstein

Goss

Hatzistergos

et al. 2014

J of Comparative Neurology

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The olfactory epithelium houses chemosensory neurons, which transmit odor information from the nose to the brain. In adult mammals, the olfactory epithelium is a uniquely robust neuroproliferative zone, with the ability to replenish its neuronal and non-neuronal populations due to the presence of germinal basal cells. The stem and progenitor cells of these germinal layers, and their regulatory mechanisms, remain incompletely defined. Here we show that progenitor cells expressing c-Kit, a receptor tyrosine kinase marking stem cells in a variety of embryonic tissues, are required for maintenance of the adult neuroepithelium. Mouse genetic fate-mapping analyses show that embryonically, a c-Kit (+) population contributes to olfactory neurogenesis. In adults under conditions of normal turnover, there is relatively sparse c-Kit (+) progenitor cell (ckPC) activity. However, after experimentally induced neuroepithelial injury, ckPCs are activated such that they reconstitute the neuronal population. There are also occasional non-neuronal cells found to arise from ckPCs. Moreover, the selective depletion of the ckPC population, utilizing temporally controlled targeted diphtheria toxin A expression, results in failure of neurogenesis after experimental injury. Analysis of this model indicates that most ckPCs reside among the globose basal cell populations and act downstream of horizontal basal cells, which can serve as stem cells. Identification of the requirement for olfactory c-Kit expressing progenitors in olfactory maintenance provides new insight into the mechanisms involved in adult olfactory neurogenesis. Additionally, we define an important and previously unrecognized site of adult c-Kit activity.

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p63 Regulates Olfactory Stem Cell Self-Renewal and Differentiation

Cited by 113 publications

References 57 publications

p63-expressing cells are the stem cells of developing prostate, bladder, and colorectal epithelia

p63-expressing cells are the stem cells of developing prostate, bladder, and colorectal epithelia

Horizontal Basal Cell-Specific Deletion ofPax6Impedes Recovery of the Olfactory Neuroepithelium Following Severe Injury

Adult c‐Kit(+) progenitor cells are necessary for maintenance and regeneration of olfactory neurons

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