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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.

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

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  1. 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

  2. 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

  3. (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

  4. 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

  5. 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

  6. 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

  7. Claudia Winograd, MD/PhD student

  8. 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

  9. 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

  10. X X X P30 P60 Adult Timeline for song learning Brainard &Doupe 2002 Nature www.eko.uj.edu.pl/ rutkowska

  11. Fmrp is increased in premotor nucleus RA P30 P60 Adult Fmrp NeuN Bar = 100um Winograd, Clayton, Ceman, 2008 Neuroscience

  12. P30 P60 Adult P60 Adult P30 TguFmrp expression in male RA changes with development Bar = 200um Winograd, Clayton, Ceman, 2008 Neuroscience

  13. 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

  14. 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

  15. 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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