Molecular Regulation of Development

Question 1

Transcription factors

Answer 1

– Proteins with domains that bind to promoter or enhancer regions & domains that interacts with RNA polymerase II – Regulates the amount of mRNA that the gene produces

Question 2

Signaling molecules

Answer 2

– Paracrine signaling or interactions: proteins secreted by one cell diffuse over a short distance to interact with another cell(s) – Includes the signaling molecule (ligand) and the receptor – A large proportion can be grouped as growth and differentiation factors (GDFs)

Question 3

Homeodomain Proteins (transcription factors)

Answer 3

Proteins with highly conserved homeodomain of 60 amino acids, which is a type of helix-loop-helix region (3 alpha-helices)

• A homeobox is a DNA sequence found within genes
  that are involved in the regulation of patterns of
  anatomical development (morphogenesis)

Question 4

Hox genes (or HOX genes)

Answer 4

• Play prominent role in
craniocaudal
segmentation of the body
• Spatiotemporal
expression proceeds
according to remarkably
regular roles
• Genes are activated &
expressed in strict
sequence in the 3’ to 5’
direction
• 3’ genes are expressed
earlier/more anteriorly
than 5’ genes (later/more
posteriorly)

• Primary function in setting up structures along the
main body axis.
• Regulation is complex
• Major regulator is retinoic acid (Vitamin A)

Question 5

What does Paralogous mean?

Answer 5

Genes related
by duplication within a
genome. They evolve new
functions, even if these
are related to the original
one.

Question 6

What are Hox gene mutations related to?

Answer 6

Hox gene mutations related to ribs and
vertebrae.

Question 7

What is Pax Gene Family?

Answer 7

• All Pax proteins contain paired domain of 128 amino acids
which binds to DNA.
• Plays a critical role in the formation of tissues and
organs during embryonic development.
• The PAX gene family is also important for maintaining
the normal function of certain cells after birth.
• Display a variety of important roles in developing nervous
system/sense organs
• Outside CNS, involved in cellular differentiative processes
when epithelial-mesenchyme transitions occur.

Question 8

What is Aniridia?

Answer 8

PAX gene disorder.

• Eye disorder characterized by a complete or partial absence of
the colored part of the eye (the iris).
• Caused by mutations in the PAX6 gene. The PAX6 gene provides
instructions for making a protein that is involved in the early
development of the eyes, CNS, and the pancreas.

Question 9

What are Lim Proteins?

Answer 9

• Large family of homeodomain proteins
• Some bind to DNA in nucleus; others are localized in the
cytoplasm
• Involved in formation of virtually all body segments
• Absence of certain Lim proteins results in development of
headless mammalian embryos.

Question 10

What are Dlx genes?

Answer 10

• Important role in patterning of outgrowing appendages in
early embryogenesis
• Also involved in morphogenesis of the jaws and inner
ear

Question 11

What are Msx genes?

Answer 11

• Prenatally – general inhibitors of cell differentiation
• Postnatally – maintain proliferative capacity of tissues
• Involved in epithelial- mesenchymal interactions in face &
limbs

Question 12

What is T-box (Tbx ) Gene Family?

Answer 12

• Named for brachyury (T) locus (causes short tails in heterozygous mice), Brakhus = short; ouras =
tail.
• Found in all bilaterians & cnidaria (corals, jellyfish)
• Important in mesodermal germ layer development
• Also important in specifying whether limbs will be forelimb or hindlimb

Question 13

(Basic) Helix-Loop-Helix
Transcription Factors

Answer 13

• 2 alpha-helices separated by a
short amino acid loop with adjacent basic regions.
• In general, transcription factors including this domain are
dimeric, each with one helix containing basic amino acid
residues that facilitate DNA binding.
• This configuration is common in transcription factors that
regulate myogenesis (formation of muscle tissue).

Question 14

What is Forkhead (Fox) Gene Family?

Answer 14

• Another large family of transcription factors (> 100)
• Regulate the expression of genes involved in cell
growth, proliferation, differentiation & longevity
• Have “pioneering transcription activity’ by being able
to bind condensed chromatin during cell
differentiation
• Defining feature is the forkhead box (winged helix)

Fox genes are expressed in many
developing organs. They tend to
have microscopically distinct
domains within an organ & can
work together to to direct
morphogenesis

Question 15

What are Transcription Factors: Zinc
Finger Proteins?

Answer 15

• Proteins with regularly placed cystidine & histidine
units bound by zinc ions
• Factors that regulate myogenesis
• Configuration causes polypeptide chain to pucker and
to produce fingerlike structures.
• These fingers’ can be inserted into specific regions in
the DNA helix.
• Implicated in bone, cartilage, or tooth development
• Zinc deficiency is known to result in skeletal growth
retardation and has been identified as a risk factor in
the pathogenesis of osteoporosis

Question 16

What are ZF-TF: Sox genes?

Answer 16

• Bind to the minor groove in DNA, and belong to a
super-family of genes characterized by a homologous
sequence called the HMG-box (for high mobility
group).
• Mutations in these genes lead to disorders that
involve the abnormal development of tissues in
which a particular SOX gene is expressed.
• SoxA = SRY, sex deterimining region of Y chromosome
• The genetic disorders caused by SOX mutations
typically have a wide variety of signs and symptoms.

Question 17

Campomelic dysplasia

Answer 17

• Caused by mutations in or near the SOX9 gene
• Effects skeleton development, reproductive and
respiratory systems & face.
• Short legs, dislocated hips, underdeveloped shoulder
blades, 11 pairs of ribs, bone abnormalities in the
neck, and inward- and clubfeet
• Ambiguous genitalia
• Larygeotracheal malacia (softened cartilage in
respiratory system)

Question 18

ZF-TF: WT1

Answer 18

• Wilm’s tumor suppresor gene
• Isolated gene
• Plays a role in kidney and gonadal development
• Also found in Denys-Drash syndrome and Frasier
syndrome, both characterized by urogenital
abnormalities, sometimes in combination with Wilm’s tumor

Question 19

What is TGF – Beta Superfamily?

Answer 19

Transforming Growth Factor

• BMP-4
  Inhibits
  neural formation
• Signaling molecules probably do not act directly on the ectodermal cells, but instead function to block the action of an inhibitor of neural formation (like BMP-4).

If BMP4 is present, ectoderm becomes epidermis
If BMP4 is blocked, ectoderm forms neural plate

Question 20

What are Fibroblast Growth Factors
(FGFs)?

Answer 20

• Broad spectrum of roles in angiogenesis, wound
healing, embryonic development and various
endocrine signaling pathways
• Secreted FGFs are closely associated with the
ECM & must bind to heparan sulfate to activate
their receptors
• Multiple methods of regulation
• Bottom line: “Variation!”

Question 21

What are Hedgehog Proteins?

Answer 21

• Desert, Indian & Sonic
• SHH-protein, bound to cholesterol & secreted
• On surface of target cell it binds to receptor, Patched (PTCH)
• Patched is bound to transmembrane protein, Smoothened
(SMO)
• It plays a key role in regulating vertebrate organogenesis, facial
& limb patterning & organization of the brain.
• SHH remains important in the adult. It controls cell division of
adult stem cells and has been implicated in development of
some cancers

Question 22

What is Indian Hedgehog?

Answer 22

It is involved in chondrocyte
differentiation, proliferation and
maturation especially during
endochondral ossification.

Question 23

What is Desert Hedgehog?

Answer 23

Defects associated with partial
gonadal dysgenesis (PGD) accompanied
by polyneuropathy.

Question 24

What is the Wnt Family?

Answer 24

Have dramatically different roles in different classes of
vertebrates
• Mammals – important in gastrulation and organogenesis
• Also often interact with ECM components & regulate cell-to-cell
interactions during embryogenesis
• Wnt proteins bind to receptors of the Frizzled and LRP families on the cell surface. Through several cytoplasmic relay
components, the signal is transduced to beta-catenin, which
enters the nucleus and forms a complex with TCF to activate transcription of Wnt transcription genes.

• Activity can be regulated by other inhibiting molecules

Question 25

What is Retinoic Acid?

Answer 25

• Metabolite of Vitamin A

• Know for decades that severe deficiencies or
excesses of Vitamin A (retinol) resulted in a broad
spectrum of abnormalities

• During early embryonic development, retinoic acid
generated in a specific region of the embryo helps
determine position along the embryonic
anterior/posterior axis by serving as an intercellular
signaling molecule that guides development of the
posterior portion of the embryo.

• It acts through Hox genes, which ultimately control
anterior/posterior patterning in early
developmental stages.

Question 26

What are Proto-oncogenes?

Answer 26

• Code for proteins that help to regulate cell growth
and differentiation.
• Are often involved in signal transduction and
execution of mitogenic signals, usually through
their protein products.
• Upon activation, a proto-oncogene (or its product)
becomes a tumor-inducing agent, an oncogene.

Question 27

What are Tumor Suppressor Genes?

Answer 27

• Normally function to limit the frequency of
• Recessive loss-of-function alleles of these genes fail
to suppress cell division, resulting in uncontrolled
division
• Example: Patched (PTCH) is the transmembrane
receptor for SHH
• Patched inhibits SMO
• Mutations of PTCH eliminate inhibition of SMO,
uncontrolled activity of SMO
• Stimulates genome of affected cells
• PTCH mutation is the basis for basal cell carcinoma