Cerebellar Deficits and Hyperactivity in Mice Lacking Smad4

Zhou, Yong; Zhao, Mingrui; Li, Dan; Shimazu, Kazuhiro; Sakata, Kazuko; Deng, Chu Xia; Lu, Bai

doi:10.1074/jbc.m308287200

Cited by 66 publications

(65 citation statements)

References 72 publications

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“…Consistent with results from previous pan-neuronal deletion of Smad4 (Zhou et al, 2003), we found no significant difference in hippocampal long-term synaptic plasticity between Smad4 KO mice and control mice. Smad4 KO mice showed both normal early-phase LTP and late-phase LTP in the CA1 region of hippocampus (Fig.…”

Section: Conditional Deletion Of Smad4 In the Mouse Forebrain Did Notsupporting

confidence: 81%

Canonical TGF-β Signaling Is Required for the Balance of Excitatory/Inhibitory Transmission within the Hippocampus and Prepulse Inhibition of Acoustic Startle

Sun¹,

Gewirtz²,

Bofenkamp³

et al. 2010

J. Neurosci.

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Smad4 is a unique nuclear transducer for all TGF-␤ signaling pathways and regulates gene transcription during development and tissue homeostasis. To elucidate the postnatal role of TGF-␤ signaling in the mammalian brain, we generated forebrain-specific Smad4 knockout mice. Surprisingly, the mutants showed no alteration in long-term potentiation and water maze, suggesting that Smad4 is not required for spatial learning and memory. However, these mutant mice did show enhancement of paired-pulse facilitation in excitatory synaptic transmission and stronger paired-pulse depression of GABA A currents in the hippocampus. The alteration of hippocampal electrophysiology correlated with mouse hyperactivity in homecage and open field tests. Mutant mice also showed overgrooming as well as deficits of prepulse inhibition, a widely used endophenotype of schizophrenia. With a specific real-time PCR array focused on TGF-␤ signaling pathway, we identified a novel regulation mechanism of the pathway in the hippocampal neurons, in which Smad4-mediated signaling suppresses the level of extracellular antagonism of TGF-␤ ligands through transcriptional regulation of follistatin, a selective inhibitor to activin/TGF-␤ signaling in the hippocampus. In summary, we suggest that the canonical TGF-␤ signaling pathway is critical for use-dependent modulation of GABA A synaptic transmission and dendritic homeostasis; furthermore, a disruption in the balance of the excitatory and inhibitory hippocampal network can result in psychiatric-like behavior.

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Section: Conditional Deletion Of Smad4 In the Mouse Forebrain Did Notsupporting

confidence: 81%

Canonical TGF-β Signaling Is Required for the Balance of Excitatory/Inhibitory Transmission within the Hippocampus and Prepulse Inhibition of Acoustic Startle

Sun¹,

Gewirtz²,

Bofenkamp³

et al. 2010

J. Neurosci.

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show abstract

“…We cannot, however, rule out the possibility that a low level of BMP signaling is occurring that falls below the threshold of our phospho-Smad immunohistochemistry. Furthermore, condi-tional inactivation of the BMP signaling mediator Smad4 in postnatal animals results in Purkinje cell loss, suggesting that BMP signaling may be required for Purkinje cell maintenance (Zhou et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Genetic Analyses Demonstrate That Bone Morphogenetic Protein Signaling Is Required for Embryonic Cerebellar Development

Qin

Wine‐Lee²,

Ahn³

et al. 2006

J. Neurosci.

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The cerebellum has been a useful model for studying many aspects of neural development because of its relatively simple cytoarchitecture and developmental program. Yet, the genetic mechanisms underlying early differentiation and patterning of the cerebellum are still poorly characterized. Cell expression studies and culture experiments have suggested the importance of bone morphogenetic proteins (BMPs) in development of specific populations of cerebellar neurons. Here, we examined mice with targeted mutations in the BMP type I receptor genes Bmpr1a and Bmpr1b, to genetically test the hypothesis that BMPs play an inductive role in the embryogenesis of cerebellar granule cells. In Bmpr1a;Bmpr1b double knock-out mice, severe cerebellar patterning defects are observed resulting in smaller cerebella that are devoid of foliation. In mutants containing either single BMP receptor gene mutation alone, cerebellar histogenesis appears normal, thereby demonstrating functional redundancy of type I BMP receptors during cerebellar development. Loss of BMP signaling in double mutant animals leads to a dramatic reduction in the number of cerebellar granule cells and ectopic location of many of those that remain. Molecular markers of granule cell specification, including Math1 and Zic1, are drastically downregulated. In addition, Purkinje cells are disorganized and ectopically located, but they appear to be correctly specified. Consistent with the interpretation that granule cells alone are affected, phosphorylated Smad1/5/8 is immunolocalized predominantly to granule cell precursors and not appreciably detected in Purkinje cell precursors. This study demonstrates that BMP signaling plays a crucial role in the specification of granule cells during cerebellar development.

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“…Down-regulation of TGF-b family signaling by a reduction in Smad4 during embryogenesis is required for proper temporal and spatial development of granule progenitor cells (Fernandes et al 2012). However, inactivation of Smad4 in the mouse CNS results in a marked decrease in the number of Purkinje cells and parvalbumin-positive interneurons in the cerebellum (Zhou et al 2003). Taken together, members of the TGF-b family directly regulate various cell types in the cerebellum.…”

Section: Hindbrainmentioning

confidence: 99%

TGF-β Family Signaling in Neural and Neuronal Differentiation, Development, and Function

Meyers

Kessler

2017

Cold Spring Harb Perspect Biol

137

107

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Cerebellar Deficits and Hyperactivity in Mice Lacking Smad4

Cited by 66 publications

References 72 publications

Canonical TGF-β Signaling Is Required for the Balance of Excitatory/Inhibitory Transmission within the Hippocampus and Prepulse Inhibition of Acoustic Startle

Canonical TGF-β Signaling Is Required for the Balance of Excitatory/Inhibitory Transmission within the Hippocampus and Prepulse Inhibition of Acoustic Startle

Genetic Analyses Demonstrate That Bone Morphogenetic Protein Signaling Is Required for Embryonic Cerebellar Development

TGF-β Family Signaling in Neural and Neuronal Differentiation, Development, and Function

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