Genes & Environment in Prenatal Development

1. PSYCH 125 Genetic & Environmental
Influences on Early Brain Development

2. From last class: Patterning of the nervous system
Concentration
gradient(s) of signaling
molecules known as
morphogens
Neural tube
The morphogens activate various
transcription factors in a
spatially specific manner.
These transcription factors bind to
specific sites in DNA sequence &
“turn genes on/off”, patterning the
nervous system

3. How is that gradient of signaling molecules set up??
We’ll get there. First, some definitions:
• Morphogen
• Transcription and Translation of DNA
• Transcription Factor

4. Morphogens
• A signaling molecule that acts directly on cells to produce specific
cellular responses dependent on morphogen concentration
• French Flag Model by famous biologist Lewis Wolpert, 1960s:
• High [ ] of morphogen activates blue gene
• Medium [ ] activates white gene
• Low [ ] is below threshold to activate
either, and red is the default color
Source: Wikipedia

5. “transcription” “translation”
DNA messenger RNA (mRNA) protein

6. Transcription factors
• Also known as sequence-specific DNA-binding
factors
• A protein that controls gene transcription by binding
to a specific DNA sequence (often within the
promoter region of a gene)

7. But where do these gradients of morphogens come
from??
Nobel Prizewinner Eric
Wieschaus, Princeton
talking about embryonic
development in
Drosophila
http://www.youtube.com
/watch?v=Ncxs21KEj0g
The story begins before fertilization…

8. Source of protein gradients in the
Drosophila oocyte
1. mRNA molecules coming from the mother are anchored to
different parts of the inside of the egg when it is first created.
2. After fertilization, they produce protein, which diffuses along the
anterior-posterior axis. So physical parameters like rate of diffusion
have important consequences for embryonic development!

9. Bicoid protein activates transcription factors in the head
Bicoid homologues are found in vertebrates

10. Sonic hedgehog (Ssh)
a morphogen that
organizes the neural tube
along the dorsal-ventral
axis in mammals

11. What would happen without sonic hedgehog?

12. Hox genes produce developmental regulatory
proteins (transcription factors high in the chain of
command) that define regions within an embryo

13. Mutations in Hox genes could explain rapid
evolutionary changes, e.g. from dinosaur to bird

14. Developmental Regulatory Genes (transcription
factors at the top of the chain of command)
http://www.youtube.com/watch?

15. The full video is worth watching!
http://www.youtube.com/watch?
v=9sjwlxQ_6LI
1) EVO/DEVO - 00:51
2) Developmental Regulatory
Genes - 2:00
3) Gap Genes - 2:39
4) Homeobox / HOX Genes - 2:50
5) Messed-Up Experiment - 6:16
6) EVO/DEVO & Evolution - 7:26
a) Chickens with teeth - 8:14

16. Quiz
Pick the best definition of a transcription factor:
A)A protein that acts directly on cells to produce specific cellular responses
dependent on morphogen concentration
B)A protein that defines regions within an embryo
C)A protein that regulates gene expression
D)A protein that regulates the assembly of proteins from mRNA

17. Astonishing progress in genetics research
A is the hereditary material
quencing of human genome completed (< 60 yrs lat
Francis S. Collins et al., Nature 422, 835-847(24 April 2003)

18. Gene variants across individuals: SNPs

19. But genes aren’t everything…
Venter, 1998: “Knowledge of the genes
will change the future of humanity”
Venter, 2010: “We have learned
nothing from the human genome.”

20. Your phenotype is a product of your genotype
and your environment

21. Epigenetics
“Nature vs. Nurture” is the wrong question…
Of course, genes are important, but the environment regulates which genes are
expressed & when (epigenetics)
Michael Meaney Megan Gunnar Charles Nelson III Nathan Fox

22. Origin of the term “epigenetics”
Conrad Waddington
coined the term
“epigenetics” in 1942
to refer to a phenomenon
that could not be
explained by genetic
principles: cellular
differentiation (how can
there be so many cell
types in the body when
they all share the same
genetic material?)
Goldberg, Allis, & Bernstein, Cell, 2007

23. Modern definition of epigenetics
“Epigenetics, in a broad sense, is a bridge between
genotype and phenotype—a phenomenon that changes
the final outcome of a locus or chromosome without
changing the underlying DNA sequence.”
“More specifically, epigenetics may be defined as the
study of any potentially stable and, ideally, heritable
change in gene expression or cellular phenotype that
occurs without changes in Watson-Crick base-pairing of
DNA.”
Goldberg, Allis, & Bernstein, Cell, 2007

24. Epigenetic influences on protein expression in neurons

25. Nutrients, toxins, stress hormones, etc. travel into
fetal blood stream from the placenta

26. Epigenetic modifications can be transmitted to the
2nd generation!
i.e., what you
experience can affect your child…
mothy G. Dinan, John Cryan, Fergus Shanahan, P. W. Napoleon Keeling & Eamonn M. M. Quigley
ature Reviews Gastroenterology & Hepatology 7, 465-471

27. Quiz
Which of the following statements about the phenomenon of epigenetics is
FALSE?
A) It alters whether/when a gene is expressed, and can even shut a gene off
forever
B) It changes the base pair sequence that constitutes a gene
C) It explains why identical twins have different phenotypes
D) It explains how maternal stress could affect the developing fetus

28. Environmental causes of birth defects
• Environmental factors only considered as contributing to abnormalities in 1940s;
before that, assumed everything was hereditary.
• N. Gregg discovered that German measles contracted by pregnant woman could
cause abnormalities in fetus
• In 1961, W. Lenz linked the sedative thalidomide to birth defects, making it clear
that drugs could cross the placental barrier.
• Since then, many agents have been identified as teratogens (factors that cause
birth defects)
28

29. Sensitive period in embryonic development
Sadler, TW (2010). Medical Embryology, Eleventh Edition.

30. Nutritional effects on prenatal development

31. Folic acid & neural tube development

32. Folic acid (Folate)
Folate is a water-soluble B-vitamin.
Our main food source is from leafy
green vegetables such as broccoli or
spinach

33. Folate deficiency in utero linked to severe
language delay at age 3
• 40,000 children participating in the Norwegian Mother and Child Cohort Study. Children
of mothers who used folic acid in the period four weeks before to eight weeks after
conception had half the risk of having severe language delay at age three, compared to
children of mothers who took no folic acid in this period (even if they took other vitamins)

34. More evidence linking folate to brain function
even after early brain development
Nilsson et al., Pediatrics, 2011

35. Folate and choline are linked metabolically, and
both contribute to brain development & function
B.
C.
A.
A. Choline is acetylated to form acetylcholine, which is a growth factor for the
developing brain (as well as one of the main neurotransmitters in the brain, important for
learning & memory)
B. Choline is phosphorylated and then used to form cellular membranes that are
required for brain function.
C. Choline is a methyl-group donor that – with folate – can influence DNA methylation and
gene expression, which can, in turn, alter brain structure and function.

36. Choline
Choline is a water-soluble essential
nutrient. Common food sources are
whole eggs and fatty meats.
Vegetarians, vegans, endurance athletes, and people who drink a lot of
alcohol may be at risk for choline deficiency and may benefit from choline
supplements. In general, people who do not eat many whole eggs may have
to pay close attention to get enough choline in their diets.

37. Choline: Striking effects in rodents
• More choline (about 4x dietary levels) during days 11 to 17 of gestation in the
rodent increases hippocampal progenitor cell proliferation, decreases
apoptosis in these cells, enhances LTP in the offspring when they become
adult animals, and enhances visuo-spatial and auditory memory by as much as
30% in the adult animals throughout their lifetimes.
• Adult rodents exposed to extra choline in utero do not show decline in
memory in old age!
• Conclusion from research in rodents: during late pregnancy, when the
hippocampus is developing, maternal dietary choline supplementation or
deficiency is associated with significant and irreversible changes in
hippocampal function, including altered long-term potentiation (LTP) and
altered memory

38. Common neurotoxins

39. Fetal Alcohol Syndrome
Why would dysmorphology of the face be caus
for concern?
Facial tissue is derived from ectodermal tissue,
which is the same tissue that gives rise to the
brain…

40. Fetal alcohol exposure
• Fetal alcohol exposure is the leading known cause
of mental retardation in the Western world (Abel &
Sokol, 1987 – from Wikipedia)
• Overall incidence of alcohol-related problems is 1:100
live births
• Fetal Alcohol Spectrum Disorder (FASD) is used to
refer to any alcohol-related defects, whereas Fetal
Alcohol Syndrome (FAS) represents the severe end
of the spectrum and includes structural defects,
growth deficiency, and mental retardation
• Alcohol is worse for fetal brain development than
cocaine!

41. Quiz
Which of the following chemical compounds can travel through the umbilical
cord and influence fetal brain development?
A)Stress hormones, alcohol, cocaine, nicotine, pesticides, etc.
B)Choline, folate, and other nutrients
C)Neither A nor B: these compounds pass to the fetus from the placenta
D)Both A and B

42. Policy Implications
• The link between prenatal alcohol exposure and subsequent mental
retardation and physical anomalies has been well-documented.
• The lifetime medical and social costs of FAS are estimated to be as high
as US $800,000 per child born with the disorder
• The predominant policy response to this highly prevalent teratogen has
focused largely on public education campaigns, cautionary signs in bars,
and warning labels on bottles and cans.
• What are the benefits and limitations of this kind of policy approach?
• What other policy options are worthy of consideration, and how do they
address potential conflicts between the rights of a pregnant woman to
autonomy and the rights of a potential child to protection from harm?
Slide courtesy of Charles Nelson III

43. Next class
How did this baby’s brain
development help him to
become the famous 18-yr-old
that he is today?