Hematopoietic Cell Regulation by Rac1 and Rac2 Guanosine Triphosphatases

Gu, Yi; Filippi, Marie–Dominique; Cancelas, José A.; Siefring, Jamie E.; Williams, Emily; Jasti, Aparna C.; Harris, Chad E.; Lee, Andrew W.; Prabhakar, Rethinasamy; Atkinson, Simon J.; Kwiatkowski, David J.; Williams, David A.

doi:10.1126/science.1088485

Cited by 432 publications

(620 citation statements)

References 22 publications

Supporting

Mentioning

581

Contrasting

Unclassified

Order By: Relevance

“…Because the systemic Rac1 null mice are embryonic lethal owing to gastrulation defects, 24 to analyze the pathophysiological significance of Rac1 in early pregnancy events, we next used a progesterone receptor (Pgr)-driven Cre (Pgr cre/+ ) mouse model crossed with Rac1 floxed (Rac1 f/f ) mice to achieve uterine-selective deletion of Rac1. [25][26][27] As shown in To ascertain the stage-specific causes accounting for this obvious infertility, we subsequently analyzed the implantation status in mice missing uterine Rac1. Although all Rac1 f/f mice tested showed normal embryo implantation on day 5 morning (Figure 2j).…”

Section: Resultsmentioning

confidence: 99%

“…Rac1 f/f mice were generated as previously described. 26,27 Uterine-specific mutant mice were generated by crossing Rac1 f/f mice with Pgr Cre/+ mice. 25 All mice were housed in the animal care facility of the Institute of Zoology, Chinese Academy of Sciences, according to the institutional guidelines for the care and use of laboratory animals.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Uterine RAC1 via Pak1-ERM signaling directs normal luminal epithelial integrity conducive to on-time embryo implantation in mice

Wang

Cui

et al. 2015

Cell Death Differ

View full text Add to dashboard Cite

Successful embryo implantation requires functional luminal epithelia to establish uterine receptivity and blastocyst-uterine adhesion. During the configuration of uterine receptivity from prereceptive phase, the luminal epithelium undergoes dynamic membrane reorganization and depolarization. This timely regulated epithelial membrane maturation and precisely maintained epithelial integrity are critical for embryo implantation in both humans and mice. However, it remained largely unexplored with respect to potential signaling cascades governing this functional epithelial transformation prior to implantation. Using multiple genetic and cellular approaches combined with uterine conditional Rac1 deletion mouse model, we demonstrated herein that Rac1, a small GTPase, is spatiotemporally expressed in the periimplantation uterus, and uterine depletion of Rac1 induces premature decrease of epithelial apical-basal polarity and defective junction remodeling, leading to disrupted uterine receptivity and implantation failure. Further investigations identified Pak1-ERM as a downstream signaling cascade upon Rac1 activation in the luminal epithelium necessary for uterine receptivity. In addition, we also demonstrated that Rac1 via P38 MAPK signaling ensures timely epithelial apoptotic death at postimplantation. Besides uncovering a potentially important molecule machinery governing uterine luminal integrity for embryo implantation, our finding has high clinical relevance, because Rac1 is essential for normal endometrial functions in women. The implantation of the blastocyst into the maternal uterus is a crucial step in establishing pregnancy and thus ensuring further embryonic development. 1-3 Similar to many developmental processes, implantation involves an intricate succession of molecular and cellular interactions which must be executed within an optimal time frame. During this period, the acquisition of blastocyst implantation competency is synchronized with the establishment of uterine receptivity. [4][5][6] On the basis of previous findings, uterine sensitivity to implantationcompetent blastocysts is classically divided into three stages: pre-receptive, receptive and refractory phases. 7 In mice, prior to day 4 of pregnancy, the uterus is conventionally considered as the pre-receptive phase. On day 4 and beyond, the uterus becomes fully receptive following the priming actions of ovarian progesterone and preimplantation estrogen; whereas by late day 5, the uterus becomes refractory to initiate the implantation. 2,4,8 Upon entering the receptive phase, uterine luminal epithelium undergoes dynamic transformation. For example, on day 4 morning in mice, luminal epithelial cells cease proliferation under the dominance of increasing levels of ovarian progesterone and preimplantation estrogen. Meanwhile, the epithelial cells undergo differentiation, accompanied with a dynamic junction complex remodeling and membrane maturation, leading to a decrease of epithelial polarity approaching implantation and a cell-shape transition from...

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Uterine RAC1 via Pak1-ERM signaling directs normal luminal epithelial integrity conducive to on-time embryo implantation in mice

Wang

Cui

et al. 2015

Cell Death Differ

View full text Add to dashboard Cite

show abstract

“…Aberrant hair follicle formation and premature postnatal death upon conditional deletion of Rac1 We generated keratinocyte-specific Rac1 conditional knockout mice (K14Cre Rac1 F/F ) by crossing C57B16 mice, in which the floxed Rac1 allele contains two loxP sites flanking exon 1 (Rac1 F/F ) (Gu et al, 2003) with mice expressing the Cre recombinase in stratified epithelium under the control of the keratin14 promoter (Andl et al, 2004). The compound line K14Cre Rac1 F/ þ was backcrossed with Rac1 F/ þ to obtain K14Cre Rac1 F/F mice.…”

Section: Resultsmentioning

confidence: 99%

“…C57Bl6 mice homozygous for the floxed Rac1 gene (Gu et al, 2003) were crossed with transgenic mice expressing Cre under the control of the K14 promoter (Andl et al, 2004) to generate homozygous mice for floxed Rac1 and heterozygous for K14Cre (K14CreRac1 F/F ).…”

Section: Experimental Micementioning

confidence: 99%

Requirement of Rac1 distinguishes follicular from interfollicular epithelial stem cells

et al. 2007

View full text Add to dashboard Cite

Epithelial stem cells in the bulge region within the hair follicle maintain the cyclic hair growth, but whether these stem cells also contribute to the epidermal renewal remains unclear. Here, we observed that the conditional deletion of the Rac1 gene in the mouse skin, including the potential follicular and epidermal stem cell compartments, results in alopecia owing to defective hair development. Surprisingly, mice lacking the expression of this Rho GTPase do not display major alterations in the interfollicular skin. Furthermore, Rac1 excision from primary epithelial keratinocytes results in the inability to reconstitute hair follicles and sebaceous glands when grafted onto mice, but epithelial cells lacking Rac1 can nonetheless form a healthy epidermis. Together, these findings support the emerging view that the epidermis and the hair follicles are maintained by different epithelial stem cells, and provide evidence that the requirement for Rac1 function can distinguish these distinct stem cells populations.

show abstract

“…Rac1 À/À HSPCs show defective hematopoietic repopulation after transplantation. This has been mainly ascribed to early engraftment failure, not to defective long-term repopulation potential [14][15][16]. Impaired microlocalization has been suggested to cause this engraftment failure.…”

Section: Introductionmentioning

confidence: 99%

The Actin Polymerization Regulator WAVE2 Is Required for Early Bone Marrow Repopulation by Hematopoietic Stem Cells

et al. 2009

View full text Add to dashboard Cite

The Rho GTPase family members play essential roles in hematopoiesis. Of these, Rac1 is thought to be required for the appropriate spatial localization of hematopoietic stem and/or progenitor cells (HSPCs) within the bone marrow (BM), whereas Rac2 likely plays a role in BM retention of HSPCs. To elucidate the molecular mechanisms underlying Rac-mediated functions in hematopoietic stem cells (HSCs), we studied Wiskott-Aldrich syndrome protein family verprolin-homologous proteins (WAVEs), the specific effectors downstream of the Rac GTPases in actin polymerization. We here showed that CD34 2/low cKit 1 Sca-1 1 lineage 2 HSCs (CD34 2 KSL HSCs) express WAVE2 but neither WAVE1 nor WAVE3. Because WAVE2 knockout mice are embryonic-lethal, we utilized HSCs in which the expression of WAVE2 was reduced by small interfering RNA. We found that knockdown (KD) of WAVE2 in HSCs affected neither in vitro colony formation nor cell proliferation but did impair in vivo long-term reconstitution. Interestingly, WAVE2 KD HSCs exhibited unaltered homing but showed poor BM repopulation detected as early as day 5 after transplantation. The mechanistic studies on WAVE2 KD HSCs revealed modest but significant impairment in both cobblestone-like area-forming on stromal layers and actin polymerization upon integrin ligation by fibronectin. These results suggested that WAVE2-mediated actin polymerization, potentially downstream of Rac1, plays an important role in intramarrow mobilization and proliferation of HSCs, which are believed to be crucial steps for long-term marrow reconstitution after transplantation.

show abstract

Hematopoietic Cell Regulation by Rac1 and Rac2 Guanosine Triphosphatases

Cited by 432 publications

References 22 publications

Uterine RAC1 via Pak1-ERM signaling directs normal luminal epithelial integrity conducive to on-time embryo implantation in mice

Uterine RAC1 via Pak1-ERM signaling directs normal luminal epithelial integrity conducive to on-time embryo implantation in mice

Requirement of Rac1 distinguishes follicular from interfollicular epithelial stem cells

The Actin Polymerization Regulator WAVE2 Is Required for Early Bone Marrow Repopulation by Hematopoietic Stem Cells

Contact Info

Product

Resources

About