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Identification of Hipk2 as an essential regulator of white fat development.

ABSTRACT: Homeodomain-interacting protein kinase 2 (Hipk2) has previously been implicated in the control of several transcription factors involved in embryonic development, apoptosis, cell proliferation, and tumor development, but very little is understood about the exact mechanisms through which Hipk2 influences these processes. Analysis of gene expression in normal tissues from genetically heterogeneous mouse or human populations can reveal network motifs associated with the structural or functional components of the tissue, and may predict roles for genes of unknown function. Here we have applied this network strategy to uncover a role for the Hipk2 gene in the transcriptional system controlling adipogenesis. Both in vitro and in vivo models were used to show that knockdown or loss of Hipk2 specifically inhibits white adipose cell differentiation and tissue development. In addition, loss of Hipk2 leads to induction of pockets of multilocular brown fat-like cells in remaining white adipose depots, which express markers of brown and beige fat such as uncoupling protein 1 and transmembrane protein 26. These changes are accompanied by increased insulin sensitivity in Hipk2 knockout mice and reduced high-fat diet-induced weight gain, highlighting a potential role for this kinase in diseases such as diabetes and obesity. Our study underscores the versatility and power of a readily available tissue, such as skin, for network modeling of systemic transcriptional programs involved in multiple pathways, including lipid metabolism and adipogenesis.

SUBMITTER: Sjolund J

PROVIDER: S-EPMC4034214 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Identification of Hipk2 as an essential regulator of white fat development.

Sjölund Jonas J Pelorosso Facundo G FG Quigley David A DA DelRosario Reyno R Balmain Allan A

Proceedings of the National Academy of Sciences of the United States of America 20140430 20

Homeodomain-interacting protein kinase 2 (Hipk2) has previously been implicated in the control of several transcription factors involved in embryonic development, apoptosis, cell proliferation, and tumor development, but very little is understood about the exact mechanisms through which Hipk2 influences these processes. Analysis of gene expression in normal tissues from genetically heterogeneous mouse or human populations can reveal network motifs associated with the structural or functional com ...[more]

PMID: 24785298

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Project description:Bergmann glia facilitate granule neuron migration during development and maintain the cerebellar organization and functional integrity. At present, molecular control of Bergmann glia specification from cerebellar radial glia is not fully understood. In this report, we show that ZEB2 (aka, SIP1 or ZFHX1B), a Mowat-Wilson syndrome-associated transcriptional regulator, is highly expressed in Bergmann glia, but hardly detectable in astrocytes in the cerebellum. The mice lacking Zeb2 in cerebellar radial glia exhibit severe deficits in Bergmann glia specification, and develop cerebellar cortical lamination dysgenesis and locomotion defects. In developing Zeb2-mutant cerebella, inward migration of granule neuron progenitors is compromised, the proliferation of glial precursors is reduced, and radial glia fail to differentiate into Bergmann glia in the Purkinje cell layer. In contrast, Zeb2 ablation in granule neuron precursors or oligodendrocyte progenitors does not affect Bergmann glia formation, despite myelination deficits caused by Zeb2 mutation in the oligodendrocyte lineage. Transcriptome profiling identified that ZEB2 regulates a set of Bergmann glia-related genes and FGF, NOTCH, and TGFβ/BMP signaling pathway components. Our data reveal that ZEB2 acts as an integral regulator of Bergmann glia formation ensuring maintenance of cerebellar integrity, suggesting that ZEB2 dysfunction in Bergmann gliogenesis might contribute to motor deficits in Mowat-Wilson syndrome.SIGNIFICANCE STATEMENT Bergmann glia are essential for proper cerebellar organization and functional circuitry, however, the molecular mechanisms that control the specification of Bergmann glia remain elusive. Here, we show that transcriptional factor ZEB2 is highly expressed in mature Bergmann glia, but not in cerebellar astrocytes. The mice lacking Zeb2 in cerebellar radial glia, but not oligodendrocyte progenitors or granular neuron progenitors, exhibit severe defects in Bergmann glia formation. The orderly radial scaffolding formed by Bergmann glial fibers critical for cerebellar lamination was not established in Zeb2 mutants, displaying motor behavior deficits. This finding demonstrates a previously unrecognized critical role for ZEB2 in Bergmann glia specification, and points to an important contribution of ZEB2 dysfunction to cerebellar motor disorders in Mowat-Wilson syndrome.

Dataset Information

Identification of Hipk2 as an essential regulator of white fat development.

Publications

Identification of Hipk2 as an essential regulator of white fat development.

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