Functional and regulatory interactions between <i>Hox</i> and<i>extradenticle</i> genes

Azpiazu, Natalia; Morata, Ginés

doi:10.1101/gad.12.2.261

Cited by 69 publications

(60 citation statements)

References 58 publications

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“…They enhance the relatively nonspecific DNA-binding properties of Hox transcription factors and regulate gene expression as heterooligomeric complexes with Hox proteins (Mann 1995). TALE proteins are required for the execution of some Hox-dependent developmental programs and are implicated in leukemogenesis (Azpiazu and Morata 1998;Ryoo et al 1999;Selleri et al 2001;Manley et al 2004;Eklund 2007;Rice and Licht 2007). Notably, mutations of Hoxa9 that prevent interactions with Pbx proteins abrogate its oncogenic properties (Schnabel et al 2000).…”

mentioning

confidence: 99%

Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential

Wong¹,

Iwasaki²,

Somervaille³

et al. 2007

Genes Dev.

261

273

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Oncogenic mutations of the MLL histone methyltransferase confer an unusual ability to transform non-self-renewing myeloid progenitors into leukemia stem cells (LSCs) by mechanisms that remain poorly defined. Misregulation of Hox genes is likely to be critical for LSC induction and maintenance but alone it does not recapitulate the phenotype and biology of MLL leukemias, which are clinically heterogeneouspresumably reflecting differences in LSC biology and/or frequency. TALE (three-amino-acid loop extension) class homeodomain proteins of the Pbx and Meis families are also misexpressed in this context, and we thus employed knockout, knockdown, and dominant-negative genetic techniques to investigate the requirements and contributions of these factors in MLL oncoprotein-induced acute myeloid leukemia. Our studies show that induction and maintenance of MLL transformation requires Meis1 and is codependent on the redundant contributions of Pbx2 and Pbx3. Meis1 in particular serves a major role in establishing LSC potential, and determines LSC frequency by quantitatively regulating the extent of self-renewal, differentiation arrest, and cycling, as well as the rate of in vivo LSC generation from myeloid progenitors. Thus, TALE proteins are critical downstream effectors within an essential homeoprotein network that serves a rate-limiting regulatory role in MLL leukemogenesis.[Keywords: Leukemia stem cells; MLL; Meis1; Pbx; TALE homeodomain proteins] Supplemental material is available at http://www.genesdev.org.

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mentioning

confidence: 99%

Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential

Wong¹,

Iwasaki²,

Somervaille³

et al. 2007

Genes Dev.

261

273

View full text Add to dashboard Cite

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“…The MD743 line directs expression in the hinge and the pleural region of the wing (M.C., unpublished). The 444-Gal4 line gives an overall uniform embryonic expression (Azpiazu and Morata, 1998). The mata-Gal4VP16 Vp15 lines (a gift from Daniel St Johnston) yield maternal Gal4 expression.…”

Section: Rt-pcrmentioning

confidence: 99%

The role ofbuttonheadandSp1in the development of the ventral imaginal discs ofDrosophila

et al. 2003

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The related genes buttonhead (btd) and Drosophila Sp1 (the Drosophila homologue of the human SP1 gene) encode zincfinger transcription factors known to play a developmental role in the formation of the Drosophila head segments and the mechanosensory larval organs. We report a novel function of btd and Sp1: they induce the formation and are required for the growth of the ventral imaginal discs. They act as activators of the headcase (hdc) and Distal-less (Dll) genes, which allocate the cells of the disc primordia. The requirement for btd and Sp1 persists during the development of ventral discs: inactivation by RNA interference results in a strong reduction of the size of legs and antennae. Ectopic expression of btd in the dorsal imaginal discs (eyes, wings and halteres) results in the formation of the corresponding ventral structures (antennae and legs). However, these structures are not patterned by the morphogenetic signals present in the dorsal discs; the cells expressing btd generate their own signalling system, including the establishment of a sharp boundary of engrailed expression, and the local activation of the wingless and decapentaplegic genes. Thus, the Btd product has the capacity to induce the activity of the entire genetic network necessary for ventral imaginal discs development. We propose that this property is a reflection of the initial function of the btd/Sp1 genes that consists of establishing the fate of the ventral disc primordia and determining their pattern and growth.

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“…The demonstrated effects of Hoxb4 retroviral overexpression on stem cells in vivo can be enhanced by concomitantly decreasing intracellular levels of PBX1, a homeoprotein of the TALE subfamily and known DNA-binding cofactor of HOXB4 and other Hox proteins [10][11][12][13][14]. Upon transplantation, these Hoxb4 + antisense Pbx1 doubly transduced HSCs (thereafter called Hoxb4 hi Pbx1 lo HSCs) are significantly (20-50 times) more competitive than control Hoxb4 hi cells [15], and interestingly, their functional integrity and responsiveness to in vivo signals that regulate HSC pool size appear unperturbed (see supplementary Fig.…”

Section: Introductionmentioning

confidence: 99%

Sustained in vitro trigger of self-renewal divisions in Hoxb4hiPbx1lo hematopoietic stem cells

Cellot

Krošl

Chagraoui

et al. 2007

Experimental Hematology

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Factors that trigger and sustain self-renewal divisions in tissue stem cells remain poorly characterized. By modulating the levels of Hoxb4 and its co-factor Pbx1 in primary hematopoietic cells (Hoxb4 hi Pbx1 lo cells), we report an in vitro expansion of mouse hematopoietic stem cells (HSCs) by 10 5 -fold over 2 weeks, with subsequent preservation of HSC properties. Clonal analyses of the hematopoietic system in recipients of expanded HSCs indicate that up to 70% of Hoxb4 hi Pbx1 lo stem cells present at initiation of culture underwent self-renewal in vitro. In this setting, Hoxb4 and its cofactor did not promote an increase in DNA synthesis, or a decrease in doubling time of Sca1 + Lin − cells when compared to controls. Q-PCR analyses further revealed a down regulation of Cdkn1b (p27 Kip1 ) and Mxd1 (Mad1) transcript levels in Hoxb4 hi Pbx1 lo primitive cells, accompanied by a more subtle increase in c-myc and reduction in Ccnd3 (Cyclin D3). We thus put forward this strategy as an efficient in vitro HSC expansion tool, enabling a further step into the avenue of self-renewal molecular effectors.

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Functional and regulatory interactions between Hox andextradenticle genes

Cited by 69 publications

References 58 publications

Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential

Meis1 is an essential and rate-limiting regulator of MLL leukemia stem cell potential

The role ofbuttonheadandSp1in the development of the ventral imaginal discs ofDrosophila

Sustained in vitro trigger of self-renewal divisions in Hoxb4hiPbx1lo hematopoietic stem cells

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