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Fragile X mental retardation protein (Fmrp) expression in zebra finch brain. Stephanie Ceman, PhD Dept. of Cell and Developmental Biology Neuroscience Program and NeuroTech Group. www.joelertola.com/ tutorials/brain/gifs/Brain.gif. commons.wikimedia.org.

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fragile x mental retardation protein fmrp expression in zebra finch brain

Fragile X mental retardation protein (Fmrp) expression in zebra finch brain

Stephanie Ceman, PhD

Dept. of Cell and Developmental Biology

Neuroscience Program and NeuroTech Group

www.joelertola.com/ tutorials/brain/gifs/Brain.gif

commons.wikimedia.org

slide2

CLINICAL FEATURES of Fragile X syndrome

  • Most common form of inherited mental retardation
  • 1/4000 males and 1/8000 females
  • 1/260 women are carriers
  • Mental impairment (I.Q. 20-60)
  • Some autistic-like behavior – poor eye contact, hand-flapping, anxiety
  • Severe delays in speech and language skills
  • Subtle facial features
    • Head circumference > 50%tile
    • Long face - prominent forehead & jaw, large ears (>2 s.d. for age)
  • Features of a mild connective tissue disorder
slide3

(CGG)n

NLS

KH1

KH2

NES

RGG

111-152

206-280

281-422

425-441

526-552

111-152

206-280

281-422

425-441

527-552

A

U

G

T

A

A

6

1

4

a

m

i

n

o

a

c

i

d

s

(

6

9

k

D

)

1

2

3

4

5

6

7

8

9

1

0

1

1

1

2

1

3

1

4

1

5

1

6

1

7

3

8

k

b

FMRP

Fragile X Mental Retardation gene 1

FMR1

slide4

FMRP

FMRP

FMRP

FMRP

Model for FMRP

function in neurons

AXON

nucleus

Beckman Researchers

working on fragile X syndrome

William Greenough

Roberto Galvez

Lee Cox

Work done in collaboration with

David Clayton

DENDRITE

Spine maturation; synaptic plasticity

slide5

Rationale for studying Fmrp in the song bird zebra finch

Fragile X individuals have pronounced speech and language deficitsRoberts, et. al J. Speech Lang Hear Res, 2005; Kau, et al. Microscopy Research and Technique, 2002; Roberts, et al. . Am J Ment Retard., 2007; Bailey, et al. Am J Ment Retard., 1998; Dykens, et al. J. Autism Dev. Disord., 1993.

Zebra finch is one of a handful of vertebrates, including humans, that learns to vocally communicate. Birdsong learning is considered the closest animal equivalent to human speech acquisitionBolhuis, & Gahr, Nat Rev Neurosci, 2006; Brainard, & Doupe,. Nature, 2002; Doupe, & Kuhl, Ann. Rev Neuroscience, 1999

Song birds, like humans, learn to vocalize during a critical period during development; Wilbrecht & Nottebohm,.Ment. Retard. Dev. Disabil. Res. Rev., 2003

The neural circuits that control vocal learning in zebra finches have clear relationships to the pathways in the human brain .

Brainard and Doupe.Nature. 2002

slide6

Ho: Fmrp plays an essential role in vocal learning

Clone and analyze zebra finch Fmr1 =

Taeniopygia guttata TguFmr1 sequence

Develop an Fmrp-specific antibody

Examine where Fmrp is expressed in brain by immuno-histochemistry

4. Determine whether Fmrp expression changes during development and/or during learning and memory

www.finchworld.com

slide8

Alignment of Human, Zebra Finch, and Chicken Fm rps

H GESQKPELKAWQGMVPFVFVGTKDSIANATVLLDYHLNYLKEVDQLRLER

F ------------GMVPFVFVGTKDSITNATVLLDYHLNYLKEVDQLRLER

C ------------GMVPFVFVGTKDSITNATVLLDYHLNYLKEVDQLRLER

HLQIDEQLRQIGASSRPPPNRTDKEKSYVTDDGQGMGRGSRPYRNRGHGRR

FLQIDEQLRQIGATSRPPPNRTDKDKGYMTDDGPGLGRGSRPYRNRGHSRR

CLQIDEQLTQIGATSRPPPNRTDKDKGYMTDDGPGKGRGSRPYRNRGHSRR

HGPGYTSGTNSEASNASETESDHRDELSDWSLAPTEEERESFLRRGDGRRR

FGPGYASGTNSEASNASETESDHRDELSDWSAAPAEEERDNYLRRGDGRRR

CGPGYASGTNSEASNASETESDHRDELSDWSAAPAEEERDNYLRRGDGRRR

HGGGGRGQGGRGRGGGFKGNDDHSRTDNRPRNPREAKGRTTDGSLQIRVDC

FGGGGRGQGGRGRGG-FKGNDEQSRTDNRQRNSREAKGRTADGSLENT---

CGGGGRGQGGRGRGG-FKGNDEQSRTDNRERNSREAKGRTADGSLENT---

H CNNERSVHTKTLQNTSSEGSRLRTGKDRNQKKEKPDSVDGQQPLVNGVP

F ---------------SSEGSRLRAGKERNPKKEKTDGADAQQPLVNQVP

C ---------------SSEGSRLRAGKERNQKKEKADGADAQQPLVNGVP

HMEELVVEVRGSNGAFYKAFVKDVHEDSITVAFENNWQPDRQIPFHDVR

FMEELVVEVRGSNGAFYKAFVKDVHEDSITVSFENNWQPERQIPFHDVR

CMEELVVEVRGSNGAFYKAFVKDVHEDSITVSFENNWQPERQIPFHDVR

HFPPPVGYNKDINESDEVEVYSRANEKEPCCWWLAKVRMIKGEFYVIEY

FFPPPAGYNKDINESDEVEVYSRANEKEPCCWWLAKVRMIKGEFYVIEY

CFPPPAGYNKDINESDEVEVYSRANEKEPCCWWLAKVRMIKGEFYVIEY

HAACDATYNEIVTIERLRSVNPNKPATKDTFHKIKLDVPEDLRQMCAKE

FAACDATYNEIVTIERLRSVNPNKPATKDTFHKIKLAVPEDLRQMCAKE

CAACDATYNEIVTIERLRSVNPNKPATKDTPHKIKLAVPEDLRQMCAKG

H AAHKDFKKAVGAFSVTYDPENYQLVILSINEVTSKRAHMLIDMHFRSL

F SAHKDFKKAVGAFSVTYDSENHQLIILSINDVTTKRANMLIDMHFRSL

C SAHKDFKKAVGAFSVTYDSENHQLIILSINDVTTKRANMLIDMHFRSL

HRTKLSLIMRNEEASKQLESSRQLASRFHEQFIVREDLMGLAIGTHGAN

FRTKLSLILRNEEASKQLESSRQLASRFHEEFVVREDLMGLAIGTHGAN

CRTKLSLILRNEEASKQLESSRQLASRFHEQFVVREDLMGLAIGTHGAN

H IQQARKVPGVTAIDLDEDTCTFHIYGEDQDAVKKARSFLEFAEDVIQV

FIQQARKVPGVTAIDLDEDTCTFHIYGEDQDAVKKARSYLEFAEDVIQV

CIQQARKVPGVTAIDLDEDTCTFHIYGEDQDAVKKARSYLEFAEDVIQV

H PRNLVGKVIGKNGKLIQEIVDKSGVVRVRIEAENEKNVPQEEEIMPPN

FPRNLVGKVIGKNGKLIQEIVDKSGVVRVRIEAENDKNIPQEE------

CPRNLVGKVIGKNGKLIQEIVDKSGVVRVRIEAENDKNIPQEE------

H SLPSNNSRVGPNAPEEKKHLDIKENSTHFSQPNSTKVQRVLVASSVVA

F ------------------------------------------------

C ------------------------------------------------

RGG

KH1

epitope

KH2

90% homology to Chicken

85% homology to Human

photo from www.ncbi.nlm.nih.gov

figure adapted from Winograd et al. 2008 Neuroscience

zebra finch brain regions involved with song learning and production
Zebra finch brain regions involved with song learning and production

Posterior Pathway

Pathway for singing/Vocal Motor pathway

~ mammalian motor corticobulbar pathway

Lesions affect singing at any age

  • Pallium
  • performs functions similar to mammalian neocortex
  • Organized by nuclei

HVC

RA

LMAN

nXIIts

Area X

Anterior Forebrain Pathway

Pathway for learning song

~ mammalian cortical-basal ganglia-thalamic cortical loop

Lesions affect ability to learn song

DLM

Thalamus

By immunostaining, Fmrp is expressed in neurons in the song nuclei

slide10

X

X

X

P30

P60

Adult

Timeline for song learning

Brainard &Doupe

2002 Nature

www.eko.uj.edu.pl/ rutkowska

fmrp is increased in premotor nucleus ra
Fmrp is increased in premotor nucleus RA

P30

P60

Adult

Fmrp

NeuN

Bar = 100um

Winograd, Clayton, Ceman, 2008 Neuroscience

slide12

P30

P60

Adult

P60

Adult

P30

TguFmrp expression in male RA changes with development

Bar =

200um

Winograd, Clayton, Ceman, 2008 Neuroscience

what does elevated tgufmrp in the neuropil of ra mean

HVC

RA

LMAN

What does elevated TguFmrp in the neuropil of RA mean?
  • RA is a premotor nucleus for song production
  • There is rapid growth of HVC axons into RA ~day 30

Konishi and Akutagava, 1985

    • Ho Fmrp plays a role in synaptogenesis
  • During song learning, HVC projects to RA, which also receives input from LMAN that introduces variability into the song of juvenile birds
    • Ho Fmrp is involved in the processing that occurs in RA, thus, is increased after singing, reflecting experience dependent plasticity
slide14

Future Goals

1. Create a knockdown bird by delivering Fmrp shRNAs into the RA of developing zebra finches

2. Examine the effect of Fmrp loss on song learning

acknowledgments
Acknowledgments

UIUC

David Clayton

Sarah London

Julie George

Michael Miles

Tory Blackwell

Claudia Winograd

Stephanie Ceman

  • Funding:
  • NIH HD41591, FRAXA Research Foundation, Spastic Paralysis and Allied Diseases of the Central Nervous System Research Foundation, Neuroscience program, CMBTG, DPNTG
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