Mammary Stem Cell Self-Renewal Is Regulated by Slit2/Robo1 Signaling through SNAI1 and mINSC

Ballard, Mimmi S.; Zhu, Anna; Iwai, Naoharu; Stensrud, Michael; Mapps, Aurelia A; Postiglione, Maira Pia; Knoblich, Juergen A.; Hinck, Lindsay

doi:10.1016/j.celrep.2015.09.006

Cited by 49 publications

(68 citation statements)

References 43 publications

(59 reference statements)

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“…However, in epidermis, we and others have shown that LGN forms an apical complex with Insc, Gαi3, NuMA, dynactin and Par3 and that LGN loss leads to loss of perpendicular divisions, impaired Notch signaling and lethal defects in epidermal barrier formation and differentiation (Lechler and Fuchs, 2005;Poulson and Lechler, 2010;Williams et al, 2011Williams et al, , 2014. Similar roles for LGN in promoting perpendicular/ asymmetric divisions have been reported in retina and mammary gland (Ballard et al, 2015;Chiu et al, 2016;Lacomme et al, 2016). The molecular mechanisms that regulate the differential subcellular localization of LGN in progenitors undergoing both symmetric and asymmetric cell divisions remain largely unknown.…”

Section: Discussionmentioning

confidence: 67%

LGN plays distinct roles in oral epithelial stratification, filiform papilla morphogenesis and hair follicle development

et al. 2016

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Oral epithelia protect against constant challenges by bacteria, viruses, toxins and injury while also contributing to the formation of ectodermal appendages such as teeth, salivary glands and lingual papillae. Despite increasing evidence that differentiation pathway genes are frequently mutated in oral cancers, comparatively little is known about the mechanisms that regulate normal oral epithelial development. Here, we characterize oral epithelial stratification and describe multiple distinct functions for the mitotic spindle orientation gene LGN (Gpsm2) in promoting differentiation and tissue patterning in the mouse oral cavity. Similar to its function in epidermis, apically localized LGN directs perpendicular divisions that promote stratification of the palatal, buccogingival and ventral tongue epithelia. Surprisingly, however, in dorsal tongue LGN is predominantly localized basally, circumferentially or bilaterally and promotes planar divisions. Loss of LGN disrupts the organization and morphogenesis of filiform papillae but appears to be dispensable for embryonic hair follicle development. Thus, LGN has crucial tissuespecific functions in patterning surface ectoderm and its appendages by controlling division orientation.

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Section: Discussionmentioning

confidence: 67%

LGN plays distinct roles in oral epithelial stratification, filiform papilla morphogenesis and hair follicle development

et al. 2016

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“…Slit-Robo signaling also controls the division mode of mammary stem cells: in the absence of Robo1, symmetric divisions are favored rather than asymmetric ones (Ballard et al, 2015). This is due to an increase in the spindle apparatus protein Insc.…”

Section: Slit-robo Signaling In Organogenesismentioning

confidence: 99%

Slit-Robo signaling

2016

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Slits are secreted proteins that bind to Roundabout (Robo) receptors. Slit-Robo signaling is best known for mediating axon repulsion in the developing nervous system. However, in recent years the functional repertoire of Slits and Robo has expanded tremendously and Slit-Robo signaling has been linked to roles in neurogenesis, angiogenesis and cancer progression among other processes. Likewise, our mechanistic understanding of Slit-Robo signaling has progressed enormously. Here, we summarize new insights into Slit-Robo evolutionary and system-dependent diversity, receptor-ligand interactions, signaling crosstalk and receptor activation.

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“…Our data showing that the region between Ϫ5,382 and Ϫ4,712 bases upstream has higher promoter activity than the minimum promoter implicates a co-regulatory element that drives mouse Insc expression within the region between Ϫ5,382 and Ϫ5,066, although this region alone is not sufficient for promoter activity. While we were preparing this manuscript, Ballard et al (58) reported that SNAL1 enhances mouse Insc expression in mammary stem cells. They used a 224-bp DNA fragment containing the upstream region of human Inscuteable for luciferase assays.…”

Section: Discussionmentioning

confidence: 99%

c-Rel Regulates Inscuteable Gene Expression during Mouse Embryonic Stem Cell Differentiation

Ishibashi

Kozuki

Kamakura

et al. 2016

Journal of Biological Chemistry

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Inscuteable (Insc) regulates cell fate decisions in several types of stem cells. Although it is recognized that the expression levels of mouse INSC govern the balance between symmetric and asymmetric stem cell division, regulation of mouse Insc gene expression remains poorly understood. Here, we showed that mouse Insc expression transiently increases at an early stage of differentiation, when mouse embryonic stem (mES) cells differentiate into bipotent mesendoderm capable of producing both endoderm and mesoderm in defined culture conditions. We identified the minimum transcriptional regulatory element (354 bases) that drives mouse Insc transcription in mES cells within a region >5 kb upstream of the mouse Insc transcription start site. We found that the transcription factor reticuloendotheliosis oncogene (c-Rel) bound to the minimum element and promoted mouse Insc expression in mES cells. In addition, short interfering RNA-mediated knockdown of either mouse INSC or c-Rel protein decreased mesodermal cell populations without affecting differentiation into the mesendoderm or endoderm. Furthermore, overexpression of mouse INSC rescued the mesoderm-reduced phenotype induced by knockdown of c-Rel. We propose that regulation of mouse Insc expression by c-Rel modulates cell fate decisions during mES cell differentiation.Insc was first identified as a novel neural precursor gene in Drosophila (1). Insc protein expression has been detected in embryonic areas where cell shape changes or movement occurs (i.e. neuroectoderm, midgut primordium, and muscle precursors) (1). More precise roles have emerged for Insc protein activity based on studies using neuroblasts, stem cells found in the central nervous system of Drosophila, which undergo asymmetric cell division (2-5). In neuroblasts, Insc localizes to the apical cell cortex by directly associating with bazooka-Par6-aPKC cell polarity protein complexes, whereas cell fate determinants, such as miranda (Mira), prospero (Pros), brain tumor (Brat), and Numb, localize to the basal cortex (6 -20). Alignment of the mitotic spindle along the apical-basal polarity axis drives asymmetric cell division to produce one self-renewing neuroblast and one ganglion mother cell fated for neural differentiation by asymmetrical inheritance of cell fate determinants (6,10,11,13,21,22). Insc plays a critical role in apical-basal spindle positioning by connecting spindle capturing machineries, consisting of partner of inscuteable (Pins) and mushroom body defect (Mud), with apical bazooka-Par6-aPKC cell polarity complexes (23-26).Similar molecular machineries are conserved in neural progenitors (27, 28) and skin basal cells of mice (29 -31), whereby mouse INSC (the mouse homologue of mammalian inscuteable) regulates spindle orientation and cell fate determination together with Par-3 (vertebrate homolog of Bazooka) and LGN (vertebrate counterpart of Pins) (27-31). Previous reports show that ectopic expression of mouse INSC promotes apical-basal spindle positioning in neuronal progenitors and keratin...

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Mammary Stem Cell Self-Renewal Is Regulated by Slit2/Robo1 Signaling through SNAI1 and mINSC

Cited by 49 publications

References 43 publications

LGN plays distinct roles in oral epithelial stratification, filiform papilla morphogenesis and hair follicle development

LGN plays distinct roles in oral epithelial stratification, filiform papilla morphogenesis and hair follicle development

Slit-Robo signaling

c-Rel Regulates Inscuteable Gene Expression during Mouse Embryonic Stem Cell Differentiation

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