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Brachy-syndactyly caused by loss of Sfrp2 function.

ABSTRACT: Wnt signaling pathways are regulated both at the intracellular and extracellular levels. During embryogenesis, the in vivo effects of the secreted frizzled-related protein (Sfrp) family of Wnt inhibitors are poorly understood. Here, we show that inactivation of Sfrp2 results in subtle limb defects in mice with mesomelic shortening and consistent shortening of all autopodal elements that is clinically manifested as brachydactyly. In addition, there is soft-tissue syndactyly of the hindlimb. The brachydactyly is caused by decreased chondrocyte proliferation and delayed differentiation in distal limb chondrogenic elements. These data suggest that Sfrp2 can regulate both chondrogenesis and regression of interdigital mesenchyme in distal limb. Sfrp2 can also repress canonical Wnt signaling by Wnt1, Wnt9a, and Wnt4 in vitro. Sfrp2-/- and TOPGAL/Sfrp2-/- mice have a mild increase in beta-catenin and beta-galactosidase staining, respectively, in some phalangeal elements. This however does not exclude a potential concurrent effect on non-canonical Wnt signaling in the growth plate. In combination with what is known about BMP and Wnt signaling in human brachydactylies, our data establish a critical role for Sfrp2 in proper distal limb formation and suggest SFPR2 could be a novel candidate gene for human brachy-syndactyly defects.

SUBMITTER: Morello R

PROVIDER: S-EPMC2677682 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Brachy-syndactyly caused by loss of Sfrp2 function.

Morello Roy R Bertin Terry K TK Schlaubitz Silke S Shaw Chad A CA Kakuru Sujatha S Munivez Elda E Hermanns Pia P Chen Yuqing Y Zabel Bernhard B Lee Brendan B

Journal of cellular physiology 20081001 1

Wnt signaling pathways are regulated both at the intracellular and extracellular levels. During embryogenesis, the in vivo effects of the secreted frizzled-related protein (Sfrp) family of Wnt inhibitors are poorly understood. Here, we show that inactivation of Sfrp2 results in subtle limb defects in mice with mesomelic shortening and consistent shortening of all autopodal elements that is clinically manifested as brachydactyly. In addition, there is soft-tissue syndactyly of the hindlimb. The b ...[more]

PMID: 18446812

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Project description:The gene kcnma1 encodes the α-subunit of high-conductance calcium- and voltage-dependent K+ (BK) potassium channel. With the development of generation gene sequencing technology, many KCNMA1 mutants have been identified and are more closely related to generalized epilepsy and paroxysmal dyskinesia. Here, we performed a genetic screen of 26 patients with febrile seizures and identified a novel mutation of KCNMA1 (E155Q). Electrophysiological characterization of different KCNMA1 mutants in HEK 293T cells, the previously-reported R458T and E884K variants (not yet determined), as well as the newly-found E155Q variant, revealed that the current density amplitude of all the above variants was significantly smaller than that of the wild-type (WT) channel. All the above variants caused a positive shift of the I-V curve and played a role through the loss-of-function (LOF) mechanism. Moreover, the β4 subunit slowed down the activation of the E155Q mutant. Then, we used kcnma1 knockout (BK KO) mice as the overall animal model of LOF mutants. It was found that BK KO mice had spontaneous epilepsy, motor impairment, autophagic dysfunction, abnormal electroencephalogram (EEG) signals, as well as possible anxiety and cognitive impairment. In addition, we performed transcriptomic analysis on the hippocampus and cortex of BK KO and WT mice. We identified many differentially expressed genes (DEGs). Eight dysregulated genes [i.e., (Gfap and Grm3 associated with astrocyte activation) (Alpl and Nlrp10 associated with neuroinflammation) (Efna5 and Reln associated with epilepsy) (Cdkn1a and Nr4a1 associated with autophagy)] were validated by RT-PCR, which showed a high concordance with transcriptomic analysis. Calcium imaging results suggested that BK might regulate the autophagy pathway from TRPML1. In conclusion, our study indicated that newly-found point E155Q resulted in a novel loss-of-function variant and the dysregulation of gene expression, especially astrocyte activation, neuroinflammation and autophagy, might be the molecular mechanism of BK-LOF meditated epilepsy.

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Brachy-syndactyly caused by loss of Sfrp2 function.

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Brachy-syndactyly caused by loss of Sfrp2 function.

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