Transcript ******** Biochemistry and Molecular biology

Molecular Biology C
Conception, theory, research, and application
——Logic and LIY (Learn It Yourself)
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Sheng Zhao (赵晟), Biochemistry and Molecular Department of Medical school in
Southeast University
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Couse QQ Club: 112342994 (分子生物学C )
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Web: http://teaching.ewindup.info/
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Email: [email protected] or [email protected]
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QQ /MSN/Skype/gChat: [email protected]
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Mobile:18551669724 or 13675130010
Chapter 3: Rap A Gene Song (Disease
research and model animals)
Section 1:
How a song can change a genome
——From bird song to infant language learning (Language
learning and language disorder)
Section 2: Life rhythm
——Biological clock in photoperiod animals (endocrine cycle
and time for medicine)
Case 3:
Taking from the movie: ”Talk to her”
——Human vegetables (Animal modeling for Brain injury)
How a song can
change a genome
Language
 Human Language:
• A human capacity
• For acquiring and using complex systems of
communication
• Language development (acquiring): soak up vocabulary,
construct new sentences, invent etc.
• Communication (Using)
• Estimates of the number of languages in the world vary
between 6,000 and 7,000.
• Human language is unique because it has the properties
of productivity, recursivity, and displacement, and
because it relies entirely on social convention and
learning.
Language and Songbirds
Many religions and mythologies have considered the language of the birds
to be a symbol of great wisdom:
The Norse god Odin had two songbirds, named thought and mind, whose
daily tweets were the source of his knowledge on our mortal affairs.
Why Songbirds
 ‘Uniquely human’?
• If you’re looking for the species that most closely
matches our linguistic prowess, you have to travel to a
far more distant relative——to a family of birds known as
the songbirds.
• ~4,000 species all over the world, in which the vocal
organ is developed to produce a diverse and elaborate
bird song
• They learn songs by imitating their elders.
• Songs are passed down from one generation to the next.
• Also best equipped to learn songs in their youth
• Have to practice to develop their ability.
• Improvise and string together riffs into new songs
• Over generations modified songs turn into new dialects.
• Hard-wired with ‘speech-centers’ in brain for language
processing.
Language and Songbirds
Learn Language from Birds
 Methods:
• By measuring how the songbird’s response changes with
a new song, you can find out whether the bird can
differentiate between the songs.
• Teach grammar to the songbirds.
• The birds were not surprised to hear the new
grammatical sentences, whereas the ungrammatical
sentences would ruffle their feathers, so to speak.
 Models
• Behavior
• Neuroscience
• Genetics
Models of the songs
 How human brains uniquely recombine a finite set of sounds to
generate infinite meaning (Hauser et al., 2002).
 Another component of language, vocal learning, is also rare but
not unique to humans.
 Human speech and birdsong are the best characterized exemplars of
vocal learning, and the experimentally tractable songbird has provided
molecular and physiological insights.
 In contrast, transgenically tractable rodents are not thought to learn
their vocalizations; however, the recent discovery that male mice
produce ultrasonic sounds that are song like (Holy and Guo, 2005)
reopens the question of whether such songs are learned.
 Disease models:
• The discovery that mutations in the human gene encoding forkhead
box P2 (FOXP2), a transcription factor, result in speech and
language deficits (Lai et al., 2001; MacDermot et al., 2005)
• Complexity of language and the variety of speech and language
disorders (which affect up to 1 in 20 children)
Anatomy of the songs
avian syrinx
1 last free cartilaginous tracheal ring
2 Tympanum
3 first group of syringeal rings
4 Pessulus
5 Membrana tympaniformis lateralis
6 Membrana tympaniformis medialis
7 second group of syringeal rings
8 main bronchus
9 bronchial cartilage
Neuroscience of the songs
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Angular Gyrus
Supramarginal Gyrus
Wernicke's Area: Language comprehension
Broca's Area: Language expression
Primary Auditory Cortex
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Anterior forebrain pathway (vocal learning)
Posterior descending pathway (vocal
production)
Neuroscience of Songs
 The acquisition and learning of bird song involves a group of
distinct brain areas that are aligned in two connecting
pathways:
 Anterior forebrain pathway (vocal learning): composed
of Area X, which is a homologue to mammalian basal
ganglia; the lateral part of the magnocellular nucleus of
anterior neostriatum (LMAN), also considered a part of
the avian basal ganglia; and the dorso-lateral division of
the medial thalamus (DLM).
 Posterior descending pathway (vocal production):
composed of HVC (proper name, although sometimes
referred to as the high vocal center); the robust nucleus
of the arcopallium (RA); and the tracheosyringeal part of
the hypoglossal nucleus (nXIIts).
Bird song development timeline
Hypothetical distributions of two
behavioral phenotypes
 Vocal learning: learn to produce elaborate patterns of structurally organized
vocalizations
 Sensory (auditory) sequence learning: the ability to remember the detail of what
is heard and the order in which it was communicated
Genetics of Songs
Genetics of Songs
Genetics of Songs
• Model system:
• The first bird genome: Chicken.
• The second bird genome: Zebra finch
• The zebra finch is a tiny Australian songbird. Only the
males sing, and they learn a particular song by listening
to their fathers.
• As in all songbirds, there is a discrete area of the
forebrain called the "song control center".
• During learning, nuclei in the song control center change
in size and organization, and during adulthood, the act
of singing alters the expression of genes.
Genetics of Songs
 Comparison:
1. The genomes of the two birds, genes that are most likely to
be important in singing and learning to sing could be found.
2. The complimentary DNA from a juvenille songbird (learning
to sing) and an adult one (able to sing).
Genetics of Songs
 Comparison:
1. The genomes of the two birds, genes that are most likely to
be important in singing and learning to sing could be found.
2. The complimentary DNA from a juvenille songbird (learning
to sing) and an adult one (able to sing).
Genetics of Songs
 Comparison:
1. The genomes of the two birds, genes that are most likely to
be important in singing and learning to sing could be found.
2. The complimentary DNA from a juvenille songbird (learning
to sing) and an adult one (able to sing).
Genetics of Songs
 Comparison:
1. The genomes of the two birds, genes that are most likely to
be important in singing and learning to sing could be found.
2. The complimentary DNA from a juvenille songbird (learning
to sing) and an adult one (able to sing).
 Singing changes expression for over 800 genes in the song control center
 RNAs in the finch's auditory centers also respond in different ways as the bird
learns a song.
• Many of the RNA transcripts (40%) are non-coding, and of the RNAs that are
suppressed in response to song, the majority are non-coding.
• Also activate small ncRNAs called microRNAs.
• A potential site of action for the microRNAs aligns to an area in a human
gene, NR4A3, that encodes a transcription factor protein.
 Learning to sing is crucial for the finch.
• It is likely that the genes involved, which include genes that encode
neuronal ion channels.
• Another possible channel of evolution is gene duplications. For example the
genes PHF7 and PAK3 have been duplicated and many variants are present
in the finch's brain.
Genetics of Songs
 Genetic mapping in an unusual multigenerational family
exhibiting a monogenic communication disorder (Fisher et al.,
1998) provided the first link between FOXP2 and language (Lai et
al., 2001).
 Affected members of the “KE” family carry a heterozygous point
mutation, yielding an amino acid substitution (R553H) in the
DNA-binding domain of the FOXP2 protein.
 This tiny change correlates with a multifaceted phenotype
(Marcus and Fisher, 2003; Vargha-Khadem et al., 2005) that
includes profound deficits in learning and production of complex
sequences of mouth movements, impairing speech (verbal
dyspraxia), as well as wide-ranging problems with language,
extending beyond expressive domains (Watkins et al., 2002a).
1. FOXP2-associated human disorder
2. Human neuron-like cells to identify other elements in
FOXP2-related pathways
3. Foxp2 mutant mouse lines to study “ultrasonic mouse songs”
4. Songbirds: dynamic regulation of FoxP2 during singing