title: The WTX tumor suppressor regulates mesenchymal progenitor cell fate specification.
abstract: WTX is an X-linked tumor suppressor targeted by somatic mutations in Wilms tumor, a pediatric kidney cancer, and by germline inactivation in osteopathia striata with cranial sclerosis, a bone overgrowth syndrome. Here, we show that Wtx deletion in mice causes neonatal lethality, somatic overgrowth, and malformation of multiple mesenchyme-derived tissues, including bone, fat, kidney, heart, and spleen. Inactivation of Wtx at different developmental stages and in primary mesenchymal progenitor cells (MPCs) reveals that bone mass increase and adipose tissue deficiency are due to altered lineage fate decisions coupled with delayed terminal differentiation. Specification defects in MPCs result from aberrant β-catenin activation, whereas alternative pathways contribute to the subsequently delayed differentiation of lineage-restricted cells. Thus, Wtx is a regulator of MPC commitment and differentiation with stage-specific functions in inhibiting canonical Wnt signaling. Furthermore, the constellation of anomalies in Wtx null mice suggests that this tumor suppressor broadly regulates MPCs in multiple tissues.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Annie
authors.initials: A
authors.lastname: Moisan
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.|Department of Pathology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Miguel N
authors.initials: MN
authors.lastname: Rivera
authors.affiliation: Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors.forename: Sutada
authors.initials: S
authors.lastname: Lotinun
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Akhavanfard
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.|Department of Pathology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Coffman
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.|Department of Pathology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Cook
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Stoykova
authors.affiliation: Endocrine Unit, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Center for Regenerative Medicine, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Jesse A
authors.initials: JA
authors.lastname: Schoonmaker
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Alexa
authors.initials: A
authors.lastname: Burger
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Woo Jae
authors.initials: WJ
authors.lastname: Kim
authors.affiliation: Endocrine Unit, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Henry M
authors.initials: HM
authors.lastname: Kronenberg
authors.affiliation: Endocrine Unit, Harvard Medical School, Boston, MA 02114, USA.|Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors.forename: Roland
authors.initials: R
authors.lastname: Baron
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism*
chemical_list: D025521:Tumor Suppressor Proteins