RGD Reference Report - MEK-ERK1/2-dependent FLNA overexpression promotes abnormal dendritic patterning in tuberous sclerosis independent of mTOR. - Rat Genome Database

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MEK-ERK1/2-dependent FLNA overexpression promotes abnormal dendritic patterning in tuberous sclerosis independent of mTOR.

Authors: Zhang, L  Bartley, CM  Gong, X  Hsieh, LS  Lin, TV  Feliciano, DM  Bordey, A 
Citation: Zhang L, etal., Neuron. 2014 Oct 1;84(1):78-91. doi: 10.1016/j.neuron.2014.09.009.
RGD ID: 11565117
Pubmed: PMID:25277454   (View Abstract at PubMed)
PMCID: PMC4185153   (View Article at PubMed Central)
DOI: DOI:10.1016/j.neuron.2014.09.009   (Journal Full-text)

Abnormal dendritic complexity is a shared feature of many neurodevelopmental disorders associated with neurological defects. Here, we found that the actin-crosslinking protein filamin A (FLNA) is overexpressed in tuberous sclerosis complex (TSC) mice, a PI3K-mTOR model of neurodevelopmental disease that is associated with abnormal dendritic complexity. Both under- and overexpression of FLNA in wild-type neurons led to more complex dendritic arbors in vivo, suggesting that an optimal level of FLNA expression is required for normal dendritogenesis. In Tsc1(null) neurons, knocking down FLNA in vivo prevented dendritic abnormalities. Surprisingly, FLNA overexpression in Tsc1(null) neurons was dependent on MEK1/2 but not mTOR activity, despite both pathways being hyperactive. In addition, increasing MEK-ERK1/2 activity led to dendritic abnormalities via FLNA, and decreasing MEK-ERK1/2 signaling in Tsc1(null) neurons rescued dendritic defects. These data demonstrate that altered FLNA expression increases dendritic complexity and contributes to pathologic dendritic patterning in TSC in an mTOR-independent, ERK1/2-dependent manner.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
tuberous sclerosis  IEP 11565117protein:increased expression:prefrontal cortex (human)RGD 
tuberous sclerosis  ISOFLNA (Homo sapiens)11565117; 11565117protein:increased expression:prefrontal cortex (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Flna  (filamin A)

Genes (Mus musculus)
Flna  (filamin, alpha)

Genes (Homo sapiens)
FLNA  (filamin A)


Additional Information