Development of Multicellular Organisms-

Part 1

05.22.2023
Myungin Baek

Chapter 21
Molecular Biology
of the Cell
Sixth Edition
 Introduction

• During development a single cell divides multiple times to produce many different cell types, which are arranged in
specific patterns
‒Four processes are fundamental to animal development
Cell proliferation
Cell-cell interaction
Cell specialization(differentiation)
Cell movement

•Similar basic developmental machinery runs in various animal species to define the specialized cell types,
help create animal body patterns, etc.
‒Homologous proteins often functionally interchangeable between very different species
 Contents

Overview Of Development

Mechanisms Of Pattern Formation

Developmental Timing

Morphogenesis

Growth

Neural Development
 Contents

Overview Of Development

Mechanisms Of Pattern Formation

Developmental Timing

Morphogenesis

Growth

Neural Development
 Conserved Mechanisms Establish the Basic Animal Body Plan

• Shared anatomical features of animals develop through conserved mechanisms

‒Zygote undergoes cell cleavages to become blastula
‒During gastrulation, cells undergo migration to become gastrula, a multilayered structure
Ectoderm: external layer; gives rise to epidermis, nervous system
Endoderm: internal layer; gut, lung, liver
Mesoderm: layer between ectoderm and endoderm; muscles, connective tissues, kidney, blood
The Developmental Potential of Cells Becomes Progressively Restricted

• During development, individual cells become restricted in their developmental potential

‒Each Cell becomes determined to a certain cell type, guided by its genome, its history, and its interaction
with neighbors
 Genes Involved in Cell–Cell Communication and Transcriptional
Control Are Especially Important for Animal Development
• Three classes of genes are especially important for multicellular organization
‒Genes encoding proteins for cell-cell adhesion and cell signaling
‒Genes encoding proteins for regulation of transcription and chromatin structure
‒Non-coding RNAs
 Regulatory DNA Seems Largely Responsible for the
Differences Between Animal Species

• Gene expression is controlled by non-coding DNA elements, enhancers

‒Transcription regulators and chromatin structures regulate the activity of enhancers
spatially and temporally
‒Differences in the enhancer elements are largely responsible for differences among animal species
Coding DNA sequences are highly conserved among animal species, while noncoding regulatory DNA
is much less conserved
 Small Numbers of Conserved Cell–Cell Signaling Pathways
Coordinate Spatial Patterning

• Spatial patterning requires the cells become different according to their positions in the embryo
‒Inductive signals may involve in the spatial patterning
Cell-cell contact or diffused molecules function as the inductive signals
e.g., transforming growth factor-β (TGFβ), Wnt, Hedgehog, Notch, receptor tyrosine kinase(RTK), etc.
 Through Combinatorial Control and Cell Memory, Simple
Signals Can Generate Complex Patterns

• Huge diversity of cells could be generated by a limited number of signaling pathways

‒Three kinds of mechanisms are involved in the process
Gene family composed of genes that play different roles
Combinatorial effects of signals
Cell memory
 Morphogens Are Long-Range Inductive Signals
That Exert Graded Effects

• Morphogen is a signal molecule that diffuse out from a localized signaling source and imposes a pattern on a whole field
of cells in a concentration dependent manner
‒The speed of diffusion and half-life of the morphogen determine the range and steepness of
the gradient
Receptors on the cell surface or molecules on the extracellular matrix affect the morphogen activity
 Lateral Inhibition Can Generate Patterns of Different Cell Types

• Positive feedback mechanism can induce pattern formation

‒Small differences between neighboring cells could be amplified by lateral inhibition
Cells that both express and respond to a signal(X) inhibit the expression of X in the neighboring cell
The stronger the signal X in one cell, the weaker the expression of X in the other cell
Initial difference could be generated by external signals or random fluctuations of the system
(e.g., Notch-Delta)
 Short-Range Activation and Long-Range Inhibition Can
Generate Complex Cellular Patterns

• Short range activator and long range inhibitor could generate pattern in an otherwise homogenous fields of cells
(reaction-diffusion system)
‒e.g., evenly distributed hairs are generated by the reaction-diffusion system
 Asymmetric Cell Division Can Also Generate Diversity

• Asymmetric cell division could generate different cell types

 Initial Patterns Are Established in Small Fields of Cells
and Refined by Sequential Induction as the Embryo Grows

• Sequential induction allows for the generation of many cell types, starting from only a few
 Developmental Biology Provides Insights into Disease and
Tissue Maintenance

• Why do we need to study animal development?

‒2~5% of all human babies are born with anatomical abnormalities
Developmental biology allows us to understand the cause of the defects
‒Developmental biology gives us insights into the workings of cells and tissues in the adult body
 Overview Of Development

Mechanisms Of Pattern Formation

Developmental Timing

Morphogenesis

Growth

Neural Development
 Different Animals Use Different Mechanisms to Establish Their
Primary Axes of Polarization

• In animals three axes generally are established during development

‒Animal-vegetal (A-V) axis, in most animals defines regions that will become internal and external
‒Anteroposterior (A-P) axis specifies the location of head and tail
‒Dorsoventral (D-V) axis specifies back and belly

•For most of the animal species, the structure of the egg defines the future axes of the body
‒In the Xenopus egg, several types of mRNA are localized to the vegetal cytoplasm
VegT (involved in endoderm, mesoderm induction)
D-V axis is defined through fertilization: sperm entry induces the rotation of the outer cortex of the
egg cytoplasm; Wnt11 moves toward to the future dorsal side through the microtubule
A-P axis of the Xenopus embryo becomes specified during gastrulation
Studies in Drosophila Have Revealed the Genetic Control Mechanisms
Underlying Development

• Through a large-scale genetic screening in Drosophila, key genes regulating development were identified
‒Initial patterning of early Drosophila embryo depends on signals that diffuse through the cytoplasm of
syncytial blastoderm
No need for usual cell-cell signaling
Regions of the syncytial blastoderm communicate with transcriptional regulators that travel through
the cytoplasm
Egg-Polarity Genes Encode Macromolecules Deposited in the Egg to
Organize the Axes of the Early Drosophila Embryo

• The main axes of the Drosophila embryo are specified by the interaction between the unfertilized egg (oocyte) and the
follicle cells that surround the oocyte
‒A/P, D/V axes of embryo is defined by egg-polarity genes in the unfertilized oocyte
Egg-polarity genes were identified from mutants displaying disrupted polarity
(e.g., tail structure in both ends of the body)
Egg-polarity genes are all maternal-effect genes (expressed from the maternal genomes)
e.g., Bicoid : anterior end of the embryo
Nanos : posterior end of the embryo
Torso : terminal structure of the embryo
Toll : ventral side of the embryo (mesoderm formation in the ventral side)
 Three Groups of Genes Control Drosophila Segmentation
Along the A-P Axis

• Egg polarity genes regulate the expression of segmentation genes that define the boundaries and ground plan of the
individual segments
‒Segmentation genes are zygotic-effect genes (expressed from the zygotic genome)
Mutations in the segmentation genes alter the number of segments or their basic internal organization
‒Segmentation genes can be classified into three groups
Gap genes: define coarse A-P subdivisions of the embryo;
one or more groups of adjacent segments are missing in mutant
Pair-rule genes: mutants have a series of defects affecting alternate segments
Segment-polarity genes: in mutants, part of the segment is replaced by a mirror-image duplicate
of the rest of the segment

• Homeotic selector (Hox) genes define the differences between one segment and the next
 A Hierarchy of Gene Regulatory Interactions
Subdivides the Drosophila Embryo

• Bicoid acts as a morphogen that regulates expression of gap genes along the A-P axis in a concentration
dependent manner
•Gap genes define finer details of patterning by regulating the expression of pair-rule genes
• After cellularization, Pair-rule genes collaborate with one another and with gap genes to induce the periodic expression
of segment-polarity genes that define the internal pattern of each segment
‒Segment-polarity genes encode two signaling pathways
Wnt pathway and Hedgehog pathway
 Hox Genes Permanently Pattern the A-P Axis

• Homeotic mutations transform parts of the body into structures appropriate to other positions
‒Homeotic selector genes (Hox genes) specify the A-P characters of animal segments
8 Hox genes in fly that are clustered into two complexes:
Bithorax complex (regulates differences among thoracic and abdominal segments)
Antennapedia complex (regulates differences among head and thoracic segments)
‒ Hox proteins are transcription regulators that have a 60-amino acid long DNA-binding homeodomain,
encoded by homeobox
Hox Genes Are Expressed According to Their Order in the Hox Complex

• Hox genes expression is regulated by regulatory DNA which contains binding sites for egg-polarity proteins and
segmentation proteins
‒The order of Hox genes in the chromosome corresponds to the order of gene expression
along the A-P axis of the body
 Trithorax and Polycomb Group Proteins Enable the Hox
Complexes to Maintain a Permanent Record of Positional Information

• The spatial pattern of Hox gene expression, set up by signals acting early in development is maintained
in a long term
‒Many of the Hox proteins autoactivate the transcription of their own genes
‒Trithorax group and Polycomb group proteins leave long lasting marks of activation or repression
on Hox genes
In the function of trithorax (activation) or Polycomb (inhibition) group is defective, initial Hox genes
expression is normal but it is not maintained during development
 The D-V Signaling Genes Create a Gradient of the
Transcription Regulator Dorsal

• As with A-P axis, patterning of D-V axis in Drosophila is induced by maternal effect genes and
is further subdivided by zygotic genes
‒A protein produced by follicle cells underneath the ventral region of the embryo leads to the activation of
Toll, transmembrane receptor on the ventral side of the egg membrane
Toll regulates the localization of Dorsal (NFκB family TF) in the nuclues
Dorsal functions similarly to a morphogen in the nucleus; in the most ventral region, Dorsal activates
Twist, a mesoderm marker; in most dorsal region where Dorsal expression levels are the lowest
Decapentaplegic(DPP; TGFβ family protein) is induced; intermediate levels of Dorsal induces
Short gastrulation (Sog; antagonist of DPP; produced in the neurogenic ectoderm)
 A Hierarchy of Inductive Interactions Subdivides the
Vertebrate Embryo

• The precursors of ectoderm, mesoderm, endoderm are arranged in order along the animal-vegetal axis of the blastula
‒Endoderm derives from most vegetal region; ectoderm from most animal region; mesoderm from
middle set
Each of the territories is further subdivided along the D-V axis
‒Maternal gene products lead to the formation of signaling centers on the vegetal and dorsal sides of the
embryo
The dorsal side signaling center, the Organizer was identified from the transplantation experiment in
the early 20th century
Unlike Drosophila Syncytial embryo, fertilized egg requires extracellular signal molecules for
patterning
 A Competition Between Secreted Signaling Proteins
Patterns the Vertebrate Embryo

• Nodal (TGFβ family protein) is secreted from the vegetal pole and form concentration gradients along the A/V axis
‒High levels of Nodal activity promote the endoderm formation; low levels mesoderm
‒Lefty, a long range Nodal antagonist secreted from the vegetal pole inhibits nodal activity in the animal
pole, which promotes the ectoderm formation in the animal pole
• Chordin and Noggin, antagonists of bone morphogenetic proteins (BMPs) are secreted from the dorsal signaling center
and determines the fate along the D/V axis
 The Insect Dorsoventral Axis Corresponds to the
Vertebrate Ventral-Dorsal Axis

• The signaling systems that pattern D/V axis are similar in both vertebrates and Drosophila
‒Dpp is a member of BMP family; Sog is a homolog of Chordin
 Hox Genes Control the Vertebrate A-P Axis

• In addition to D/V signaling systems, Hox systems are similar in both vertebrates and Drosophila
‒The order of genes in each Hox complex of vertebrates is similar to that of Drosophila Hox complex
‒Also as in Drosophila, Hox genes in each complex are expressed in a series along the A-P body axis
Vertebrate Hox genes control the A-P patterns of parts in the body
(e.g., gain or loss specific Hox genes)
 Some Transcription Regulators Can Activate a Program That
Defines a Cell Type or Creates an Entire Organ

• There are genes that trigger the development of a specific cell type or a specific organ
‒MyoD/myogenin family transcription regulators drive cells to differentiate into muscle
‒Achaete/Scute family transcription regulators drive cells to become neural progenitors
‒Eyeless(Pax6) drive the formation of multiple cell types constituting an entire organ
 Notch-Mediated Lateral Inhibition Refines
Cellular Spacing Patterns

• Notch signaling is crucial for both cell diversification and fine-grained patterning
‒e.g., sensory bristles in Drosophila
Achaete and Scute(proneural genes) define the area where the bristle will form
Proneural cells express proneural genes and a single cell(sensory mother cell) within each small group
of proneural cells serves as a progenitor of the bristle; lateral inhibition mediated by Notch
makes the sensory mother cell different from other cells in the cluster