Developmental

Biology
References

Developmental Biology, Eighth Edition - Scott F Gilbert.

Essential Developmental Biology - Jonathan Slack

Developmental Biology - Werner A Muller

Principles of Development - Lewis Wolpert

Website: virtual embryo-

http://people.ucalgary.ca/~browder/virtualembryo/db_tutorial.html
 Development

Process by which a complex multi cellular

organism arises from a single cell.

Development is progressive
The main questions addressed in development

 How do cells become different from one

another and from their precursors?
(What are the the genes and molecular events that control
development ? )

How is ordered body plan generated ?

(What are the structural changes that an organism
undergoes as it develops? )

How does one generation create

another generation? (what makes germ cells
different from somatic cell?
Development spans from

DNA in the nucleus- changes among cells–

Tissues – organs – organ systems - whole
organisms.
the study of development brings together

Cell Biology: how cells change (Cell signaling)

Genetics: how genes bring about changes

Molecular Biology: how genes are turned on

and off

multidisciplinary approach
Developmental Biology is relevant to all of us.
Why?

It has far reaching impact on our understanding of

…

• How defects in development cause disease

(gene –linked diseases, drug discovery )

• The basis of many cancers. (Improvements in

cancer detection and treatment )

• How to repair when parts of the body are

not functioning (regenerative medicine, stem cell
therapy )
Historical roots of
developmental biology
theory of preformation -now discredited (
Malpighi 1694)

theory of epigenesis (Aristotle)

The study of development as we view it today
only began in the early 19th century

we could divide progress since then into 4

important phases
 Improved
Descriptive microscopes led to
reliable observation
embryology and development of
a suitable
(19th century)
vocabulary

Karl Ernst von

E.B. Wilson, 1896
Baer
development of the
( father of modern
embryo is a
Embryology)-
manifestation of
explained blastula,
changes in individual
notochord, germ
cells
layers
Experimental Embryology (Late 19th Century, early 20th century)

Manipulated embryos Wilhelm Roux 1888:

to investigate changes genetic information is
in cells and inherited equally by all
interactions between cells during development.
cells during
development

Rita Levi-Montalcini
Hans Spemann and
and Viktor Hamburger,
Hans Driesch Hilde Mangold,
1956 --- discovered
1892: separated 1924:-- did tissue
the first "growth
the cells of 2-cell transplantation
factor--- purified the
and 4-cell embryos experiments on the
factor and called it
of sea urchin amphibian Triturus
Nerve Growth Factor
(Totipotency) ---- concept of
(NGF) from mouse
embryonic induction
tumors
 Developmental Genetics (20th Century)

Theodor Boveri Thomas Hunt Morgan,

1902: 1927: experiments on
Drosophila --used ionizing
experimented
radiation to induce
The realization that with sea urchin mutations in DNA --
certain genes play eggs --- normal demonstrated that
important roles in development specific genes are located
guiding development depends on the on specific chromosomes
normal -- correlated certain
combination of developmental defects
chromosomes with mutations in certain
chromosomes
 Finding the genes-

Molecular analysing how they

work-
Developmental
what kind of gene
Genetics (From products they make -
late 1980)
how these affect
development.

Transgenics ,
Biochemical
gene
techniques to
knockouts, RT-
elucidate signal
PCR, DNA
transduction
microarrays,
pathways
RNAi
The conclusion

Genes which are expressed early in

development provide signals to direct the
expression of genes later in development

fundamentally similar mechanisms guide the

development of all organisms

Many genes involved in development are

common in insects, animals, and humans.
Eg: eyeless gene of drosophila , small eye in
mouse , aniridia of Humans

All genes are homologues and are members of

a family of homologous genes called Pax-6 , a
master control gene for eye development
(formation of retinal cells)
Basic concepts in Developmental
Biology
 Common Features of development
Fertilization- formation of zygote
Cleavage- formation of blastula
Gastrulation- formation of gastrula (triploblastic
organization)
Neurulation – formation of nervous system
(neurula)
Organogenesis –formation of individual organs
Development involves five major overlapping
processes

Cell Growth
cell division
Differentiation
Pattern formation
Morphogenesis
Growth & cell division
 In the earliest stage of animal development (
cleavage)- the cell number increases in the
absence of growth.

 Later in development ,growth can occur in the

absence of cell division
( increasing cell volume, changing cell shapes,
growth of extra cellular structures
secreted by cells etc. )
 Differentiation

 cells become structurally and functionally

specialized by synthesizing different
proteins, allowing the formation of different
cell types ( neurons, keratinocytes,
erythrocytes Etc)

 The process of differentiation involves

control and maintenance of differential gene
expression
Pattern formation

Process by which cells become organized in the

embryo ,initially to form the basic body plan,
and later to generate fine structure of
individual organs

This involves –
axis specification
positional information
 Morphogenesis (Creation of structure and
form )

how embryo progresses beyond a simple ball of

cells ?

Denotes the many different types of cell

behavior that helps to shape tissues and organs
Cell sheets Cell sheets Individual cells

Cell sheets Cell sheets Morphogenetic

behaviours of
the embryo
 Individual cells

Morphogenetic
Cell sheets behaviours of
the embryo

condensation Individual cells dispersal Individual cells

 Cellular basis of morphogenesis

Differential rates of cell division

Changing cell size & shape -by reorganizing the

cytoskeleton
Cell fusion (syncitium)
Cell death ( apoptosis )
Cell adhesion ( Cadherins, CAMs)
Cell migration ( ECM proteins & integrins)
Principles of cell differentiation
The fate (potency )
of a cell is all the different cell types its
descendants can become during normal
development

Potency of cells become increasingly restricted

until a cell is terminally differentiated.( can
form only a single cell type)
Developmental hierarchy in vertebrates

crest
In animals, these decisions are usually
irreversible.

In plants , cell fates are progressively

restricted but differentiation doesn't
correspond with terminal restriction in potency
( the cells remain totipotent even when they
have differentiated)
 Fate map

A map of an embryo or any developing

system showing which adult tissues are
formed from each region during normal
development

The term presumptive is used to describe

the fate of each region.
Fate map of frog gastrula
Commitment

As cell fate becomes restricted ,following

each decision in the developmental hierarchy,
cells are said to become committed to a
certain fate
 Specified Determined Differentiated
Naïve

Uncommitted-cell Received Fate cannot Cell specific

has not received instructions,and be changed gene
any instructions follows regardless of expression
,directing it along instructions in a the cell’s
a particular neutral environment-
developmental environment- irreversible
pathway but can be
respecified if
placed in a
different
environment
Different levels of developmental commitment
In animals ,commitment occurs in stages ,initially reversible
and then permanent
Mechanisms of cell differentiation
To differentiate, cells must begin to synthesize
new proteins

This requires selective expression or

activation of regulatory molecules (such as
transcription factors )

Regulatory molecules could be inherited as

cytoplasmic determinants, or activated by
external signals
Cytoplasmic determinants

Molecules of cytoplasm ,the polarized

distribution of which in a mother cell can
result in their inheritance by only one of the
daughter cells following cell division, thus
promoting differentiation of the daughter
cells
Eg: In Xenopus , localization of vegT mRNA
to the vegetal cortex of the egg during
development

Veg T protein activates expression of genes

encoding endoderm specific transcription
factors( Sox17)& which forms endoderm
 External signaling ( Embryonic induction)

A process by which a cell or group of cells can

influence the developmental fate of another.

The inductive signal may be a protein or another

molecule secreted from the inducing cell.

Induction can occur by endocrine/

paracrine/ autocrine /juxtacrine signaling
Competence- Ability of a cell to respond to
inductive signal.

requires specific receptors,

functioning signal transduction pathway coupled

to regulation of transcription factors

 which eventually alters the pattern of gene

expression.
Eg: Mesoderm induction in Xenopus

The nodal proteins in the endoderm induce

the expression of mesoderm –specific
transcription factors ( Brachyury) in an
equatorial belt of neighboring cells

The remainder of animal hemisphere

becomes ectoderm
Morphogen

If there is more than one positive response at

different concentrations of the inductive factor
the factor is described as a morphogen

A morphogen gradient can be set up ,and

different responses can be induced
Morphogen gradients can be established by
depending on the distance of the responding
cell from the source of the morphogen

Anti-morphogen - Inducer can be secreted

uniformly, but the level of its activity can be
graded by the diffusion of an inhibitor .

Varying the levels of the receptor in the

responding cell
Different types of embryonic induction
Instructive induction
Occurs where the responding cell has a choice
of fates and will follow one pathway in response
to induction but an alternative pathway in the
absence of induction

Eg: In Xenopus dorsal ectoderm will form

epidermis in the absence of induction ,but
neural plate in presence of inductive signals
from the notochord
Permissive induction
The responding cell is already committed to a
certain developmental fate ,and inducing
factor is necessary simply for the continued
development of the down stream cells
Eg: Myoblasts continue to proliferate until
growth factors are withdrawn ,when they
differentiate into muscle fibres

(induction can occur as well through

withdrawal of signal)
Reciprocal induction

Once the responding cells receive induction

, they can then induce back the previous
inducing tissue. ie now the inducer becomes
the induced.

Eg; formation of lens placode (lens) & optic

cup (retina) from ectoderm
Lateral inhibition
It is a type of cell–cell interaction whereby a
cell that adopts a particular fate inhibits its
immediate neighbours from doing likewise.

the trans membrane proteins Notch and Delta

(or their homologues) have been identified as
mediators of the interaction
Eg :vertebrate neurogenesis

Neuroblast with slightly more Delta protein

(due to high Math1/Ngn3) on its cell surface
will inhibit its neighboring cells from becoming
neurons.

Delta is found in those cells that will become

neurons, while Notch is elevated in those cells
that become the glial cells
In the developing mammalian nervous system, neural progenitor cells first
express the Notch effector Hes1 at variable levels and then proneural genes
and Notch ligands in salt-and-pepper patterns. Recent real-time imaging
analysis indicates that Hes1 expression in these cells oscillates with a period
of about 2–3 h. Furthermore, the proneural gene Neurogenin-2 (Ngn2) and the
Notch ligand gene Deltalike-1 (Dll1) are expressed cyclically in neural
progenitor cells under the control of Hes1 oscillation but are expressed
continuously in postmitotic neurons, which lose Hes1 expression. Hes1-driven
Ngn2 and Dll1 oscillations seem to be advantageous for maintenance of a
group of cells in an undifferentiated state by mutual activation of Notch
signaling. This dynamic mode of gene expression would require a revision of
the traditional view of how Notch-mediated lateral inhibition operates in the
developing mammalian nervous system.
Community effect
A population of cells must be present to change
the collective cell fate ( involves autocrine&
paracrine signaling )
Eg: formation of epidermis in Xenopus
Isolated ectoderm tissue from Xenopus blastula
will differentiate into epidermis, whereas
individuals cells can form neurons .
Ectoderm secretes certain bone morphogenetic
proteins (BMP) that inhibits neural differentiation
,but isolated cells do not produce enough signal
to prevent the outcome.
 Thus, cell fates can be specified by cell-cell
interactions (conditional specification and
regulative development)

or by the asymmetric distribution of patterning

molecules into particular cells (autonomous
specification and mosaic development)

Most organisms contain tissues which may

undergo one or both of these developmental
mechanisms at a given time
The predominance of each strategy varies
in different species
 Maternal & zygotic genes

Maternal effect mutations- phenotypes are

manifested in the embryos of mutant females ,but not in
the mutant females themselves
Maternal gene products ,which are active during early
development ,later they may become depleted

development then becomes dependent on zygotic gene

products and zygotic mutations that affect
development become apparent
MODEL ORGANISMS
model organism is a species that is extensively
studied to understand particular biological
phenomena, with the expectation that discoveries
made in the organism model will provide insight
into the workings of other organisms
Often used model organisms in developmental biology include the
following:

Vertebrates
Zebrafish Danio rerio
Frog Xenopus laevis
Chicken Gallus gallus
Mouse Mus musculus (Mammalian embryogenesis)

Invertebrates
Sea urchin
Round worm Caenorhabditis elegans
Fruit fly Drosophila melanogaster

Plants (Plant embryogenesis)

Arabidopsis thaliana
certain criteria are used for a model system
depending upon the experimental purposes.
1) rapid development with short life cycles,
2) small adult size
3) ready availability
4) tractability/easy to manipulate
5) Large no.of embryos
6) Easy to breed in the lab
There are two modes of development common to most species in the animal kingdom.
 Mosaic development
The fate of every cell is governed entirely by its
intrinsic characteristics,ie, the cytoplasmic determinants
it inherits at cell division ,rather than position in relation
to other cells
During development each cell undergo autonomous
specification
If isolated , each cell differentiates into appropriate
part of the embryo, and the remainder of the embryo will
develop normally ,but would lack the parts specified by
the missing cell
Regulative development
The fate of every cell is governed entirely by its
interactions with other cells
Each cells undergo conditional specification ,ie,
conditional on the presence of other cells
If removed from the embryo the given cell will not
fulfill its normal fate
The remainder of the embryo can be respecified to
fill in the missing pattern.
Eg: In Ascidians the epidermis, endoderm and most muscle
cells are specified by the distribution of cytoplasmic
determinants in the egg- the embryo shows striking mosaic
behaviour
However ,specification of other tissues like notochord, CNS
are conditional
In mammals, early development is purely regulative
,cytoplasmic determinants appear much later in mammalian
development ,during neuronal differentiation
Genes in development
Multipotent/ oligopotent/
unipotent
All the processes that are essential for development –
are mediated ultimately by proteins ,which are encoded
by genes
So development is controlled to a large degree by
gene expression ( they determine where and when
proteins are synthesized in the embryo)
Many genes, shown to have important roles in
development encode –
Transcription factors
Components of different signaling pathways
The first patterning event in the embryo -
(establishment of principal body axes)

The central nervous system defines the antero

posterior axis( brain is found at the anterior end ) (
cranio caudal/ rostro caudal)

Dorsoventral axis –runs from back to belly

Left –right axis – specified by default
Proximo- distal- limbs, eyes etc- from the body to
the extremity of the structure

Animal –vegetal axis- animal eggs- when egg is yolky

nucleus is displaced to one end
Polarization is an important part of axes
specification ,which involves a symmetry
breaking process such as
asymmetric distribution of cytoplasmic
determinants in the egg ( eg: polarization of
anteroposterior axis in drosophila embryo)
OR
an external physical cue ( eg: Anteroposterior
axis in vertebrate embryo)
Axis specification is followed by giving
positions (positional information) to cells along
each axis.( dividing axis in to different
developmental compartments or segments )
Telling each cell where it is and thus how to behave to
generate regionally appropriate structures
By giving positional value or positional identity
( role of morphogens)
compartments are fields of cells of distinct
cell lineage, cell affinity, and genetic identity.
In a developing organ , all cells within a
compartment possess similar affinities, and so
intermingle with each other.
However, cells in neighboring compartments
have different cell affinity values and so never
mix, thereby restricting the movement of cells
to within compartments.
This has the effect of forcing cell lineages to
stay within compartment boundaries.
Eg:
obvious segmentation is seen in insect & annelid
bodies
Also Rhombomeres & somites of vertebrate
embryos
1. Differential rates of cell division
Eg: In vertebrate embryo -selective growth of limb bud
rather than adjacent regions of the lateral plate
mesoderm ,by secreting certain growth factors

2. Position and orientation of mitotic spindle during cell

division
This determines the relative sizes of the daughter cells &
can influence the structure of a particular tissue
3. Changing cell size & shape
By reorganizing the cytoskeleton
Eg:invagination of epithelial cells during gastrulation

Cell size & shape can also be changed by varying the cell
volume
Eg: adipocytes grow in size as they accumulate storage
lipids
6. Cell adhesion
Cells bind together using membrane bound cell adhesion
molecules
The adhesion molecules synthesized by a particular cell
types determines the cells it can and cannot adhere to
This helps organize cells into tissues and to maintain
boundaries between different tissues
Calcium dependent cadherins & calcium independent
CAMs are two major classes of cell adhesion molecules

Eg: vertebrate development neural tube (expressing N-

cadherin) separate from the epidermal ectoderm
(expressing E-cadherin) & sinks beneath it
7. Extra cellular matrix & cell migration
Cells interact with molecules in the extra cellular matrix
through membrane bound proteins called Integrins
Different integrins have differential affinity for matrix
proteins like laminin, collagen & fibronectin
Cells may gain or lose contact with EC matrix by altering
the expression of integrin proteins
Eg: Epidermal stem cells are bound to the basal lamina.
But differentiation of keratinocytes involves down
regulation of integrin synthesis , so that young
keratinocytes detach & migrate into upper layers
Interaction between EC matrix & cells can allow cells
to move over relatively large distances during
development
Eg: long distant migration by individual cells occurs in
neural crest lineage & in the germ line
Eg: the movement of entire cell sheets occurs during
gastrulation
4. Cell fusion
This generates syncytia & is important in several
developmental processes
Eg: during muscle development myoblasts fuse to form
multi nucleated myotubes .These myotubes synthesize
muscle specific proteins & become muscle fibers

5. Cell death ( apoptosis )

Programmed cell death during development helps to
generate various organs
Eg: vertebrate limb development –apoptosis at
interdigital necrotic zones results in the separation of
digits