Mansukhani Lab - Microbiology

Alka Mansukhani
Associate Professor, Department of Microbiology

Medical Science Building
, Room 252, 207

550 First Avenue, New York, NY 10016

Office: (212) 263-5906

Fax: (212) 263-8276

Lab: (212) 263-5331


Email: alka.mansukhani@med.nyu.edu

KEY INTERESTS:

stem cells, mesenchymal stem cells, fibroblast growth factors, tyrosine kinase receptors, cell lineage fate, osteosarcoma, Wnt signaling, mouse genetics, conditional knockout, bone cells

BIOGRAPHIC DETAILS:

RESEARCH INTERESTS:

We study the signals that determine cell fate and the regulators of progenitor stem cells that determine cellular decisions  - to undergo quiescence, proliferation, or differentiation. In particular, we study the osteoblast lineage that derives from mesenchymal stem cells.  Under the influence of several signals such as FGFs, BMPs, Wnts, and IGFs, these multipotent cells become lineage restricted and give rise to osteoblasts, adipocytes, chondrocytes and myocytes that form bone, fat, cartilage and muscle respectively.

We have recently found that the stem cell transcription factor, Sox2 is needed for the survival of the osteoblast lineage. Sox2 is a known player required in embryonic stem cells to maintain pluripotency. It is one of the four factors required for reprogramming somatic cells to induced pluripotent cells. Since the total knockout of Sox2 is lethal, we have studied mice with a conditional knockout of Sox2 in osteoblasts. These mice have low bone density and reduced osteoprogenitor lineage cells. Deletion of Sox2 in osteoblast culture leads to cell senescence. Using mouse models and gene expression studies we are determining Sox2 target genes and microRNAs and the mechanisms by which Sox2 maintains progenitor cells in this lineage.

Several lines of evidence indicate that the commitment to form bone and fat are reciprocally regulated. We have demonstrated that Sox2 inhibits differentiation by interfering with Wnt signaling, which drives osteoblast differentiation and inhibits adipogenesis. We are examining the role that FGFs play in maintaining the undifferentiated state, and the role of factors such as Sox2 in regulating cell fate determination.

We also study the role of FGF and Sox2 in cancer, particularly in osteosarcomas,  which are bone tumors that arise from osteoprogenitor cells that no longer heed the signals to differentiate.    In osteosarcomas, Sox2 inhibits Wnt signaling to maintain the undifferentiated and tumorigenic state.  Our studies are directed at understanding the dysregulation that leads to these tumors.

PUBLICATIONS:

Distinct functions of Sox2 control self-renewal and differentiation in the osteoblast lineage.
Seo, E., Basu-Roy U, Zavadil J, Basilico C, Mansukhani A (2011)
Mol Cell Biol. Nov;31(22):4593-608.  Supplementary data. PMID:21930787.

Sox2 maintains tumor initiating cells  in osteosarcoma. 
Basu-Roy U, Seo E, Ramanathapuram L, Rapp TB, Perry J, Orkin, S, Mansukhani A and Basilico C (2011)
Oncogene. Sep 19. doi: 10.1038/onc.2011.405. PMID:21927024

The transcription factor Sox2 is required for osteoblast self-renewal.
Basu-Roy U, Ambrosetti, A, Favaro R, Nicolis, SK, Mansukhani A and Basilico C (2010)
Cell Death and Differentiation. Aug;17(8):1345-53. Epub 2010 May 21.
PMID: 20489730

Early onset of craniosynostosis in an Apert mouse model reveals critical features of this pathology.
Holmes G, Rothschild G, Roy UB, Deng CX, Mansukhani A, Basilico C (2009)
Dev. Biol. Apr 15;328(2):273-84. Epub 2009 Jan 29.

PMID: 19389359

Fibroblast growth factor signaling uses multiple mechanisms to inhibit Wnt-induced transcription in osteoblasts.
Ambrosetti D, Holmes G, Mansukhani A, Basilico C (2008)
Mol Cell Biol. Aug;28(15):4759-71.

PMID: 18505824

"Osteoblast proliferation or differentiation is regulated by relative strengths of opposing signaling pathways".
Raucci A; Bellosta P; Grassi R; Basilico C; Mansukhani A (2008)
Journal of Cellular Physiology. May;215(2):442-51. 

PMID: 17960591

"Enhanced Paracrine FGF10 Expression Promotes Formation of Multifocal Prostate Adenocarcinoma and an Increase in Epithelial Androgen Receptor".
Memarzadeh S, Xin L, Mulholland DJ, Mansukhani A, Wu H, Teitell MA, Witte ON (2007)
Cancer cell. Dec; 12: 572 (#J0132178)

PMID: 18068633

Mechanisms underlying differential responses to FGF signaling.
Dailey L, Ambrosetti D, Mansukhani A, Basilico C (2005)
Cytokine Growth Factor Rev. Apr;16(2):233-47. Review.

PMID: 15863038

Sox2 induction by FGF and FGFR2 activating mutations inhibits Wnt signaling and osteoblast differentiation.
Mansukhani A, Ambrosetti D, Holmes G, Cornivelli L, Basilico C (2005)
J Cell Biol. Mar 28;168(7):1065-76.

PMID: 15781477

Activation of the ERK1/2 and p38 mitogen-activated protein kinase pathways mediates fibroblast growth factor-induced growth arrest of chondrocytes.
Raucci A, Laplantine E, Mansukhani A, Basilico C (2004)
J Biol Chem. Jan 16;279(3):1747-56.

PMID: 14593093

p21(WAF1/CIP1) acts as a brake in osteoblast differentiation.
Bellosta P, Masramon L, Mansukhani A, and Basilico C (2003)
J Bone Miner Res. May;18(5):818-26.

PMID: 12733720

Role of Fibroblast Growth Factor Receptor Signaling in Prostate Cancer Cell Survival.
Ozen M, Giri D, Ropiquet F., Mansukhani A and Ittmann M (2001)
J Natl Cancer Inst. Dec 5;93(23):1783-1790.

PMID: 11734594

Increased expression of fibroblast growth factor 6 in human prostatic intraepithelial neoplasia and prostate cancer.
Ropiquet F, Giri D, Kwabi-Addo B, Mansukhani A and Ittmann M (2000)
Cancer. Res. Aug 1;60 (15):4245-50.

PMID: 10945637


Signaling by fibroblast growth factors (FGF) and fibroblast growth factor receptor 2 (FGFR2)-activating mutations blocks mineralization and induces apoptosis in osteoblasts.
Mansukhani A, Bellosta P, Sahni M, Basilico C (2000)
J Cell Biol. Jun 12;149(6):1297-308.

PMID: 10851026

FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway.
Sahni M, Ambrosetti DC, Mansukhani A, Gertner R, Levy D, Basilico C (1999)
Genes Dev. June 1;13(11):1361-6.

PMID: 10364154

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