Download Bicoid gene

Multicellular development and
morphogens
Development is the successive process of
systematic gene-directed changes
throughout an organism’s life cycle
-Can be divided into four sub-processes:
-Growth (cell division)
-Differentiation
-Pattern formation
-Morphogenesis
Pattern formation:
• the generation of complex organizations of
cell fates (programming of a cell to follow a
specified path of cell differentiation) in space
and time.
• Pattern formation is controlled by genes .
Morphogen
• Is a substance governing the pattern of tissue
development and, in particular, the positions
of the various specialized cell types within a
tissue.
• It spreads from a localized source and forms a
concentration gradient across a developing
tissue.
Morphogenesis:
• Is developmental process by which anatomical
structures or cells shape and size are
generated and organized.
• It achieves through changes in:
-Cell division
-Cell shape and size
-Cell death
-Cell migration( animal)
• Morphogenesis is controlled by certain types
of molecules:
1) morphogens.
2) transcription factors.
3) cell adhesion molecules.
• The morphogen idea has a long history in
developmental biology, dating back to the
work of the pioneering Drosophila geneticist,
Thomas Hunt Morgan, in the early 20th
century.
• However, it was Lewis Wolpert who refined
the morphogen concept in the 1960s with his
famous French flag model which described
how morphogen could subdivide a tissue into
domains of different target gene expression
(corresponding to the colours of the French
flag).
• In developmental biology a morphogen is
rigorously used to mean a signaling molecule
that acts directly on cells (not through serial
induction) to produce specific cellular
responses dependent on morphogen
concentration.
• During early development, morphogen gradients
generate different cell types in distinct spatial order.
• The morphogen provides spatial information by forming
a concentration gradient that subdivides a field of cells by
inducing or maintaining the expression of different target
genes at distinct concentration thresholds.
• Distinct cell types emerge as a consequence of the
different combinations of target gene expression.
• In this way, the field of cells is subdivided into different
types according to their position relative to the source of
the morphogen.
• Cells far from the source of the morphogen will receive
low levels of morphogen and express only lowthreshold target genes.
• In contrast, cells close to the source of morphogen will
receive high levels of morphogen and will express both
low- and high-threshold target genes.
Mutations of HNF-1 inhibit epithelial morphogenesis
through dysregulation of SOCS-3
• Hepatocyte nuclear factor-1 (HNF-1) is a Pit-1, Oct-1/2, Unc-86 (POU)
homeodomain-containing transcription factor expressed in the kidney, liver,
pancreas, and other epithelial organs.
• Mutations of HNF-1 cause maturity-onset diabetes of the young, type 5
(MODY5), which is characterized by early-onset diabetes mellitus and
congenital malformations of the kidney, pancreas, and genital tract.
•
Knockout of HNF-1 in the mouse kidney results in cyst formation.
Zhendong Ma*, Yimei Gong*, Vishal Patel*, Courtney M. Karner*†, Evelyne Fischer‡, Thomas
Hiesberger*,Thomas J. Carroll*†, Marco Pontoglio‡, and Peter Igarashi*§¶Edited by Maurice B.
Burg, National Institutes of Health, Bethesda, MD, and approved October 25, 2007 (received for
review June 25, 2007)
Role of CDMP-1 in Skeletal Morphogenesis: Promotion
of Mesenchymal Cell Recruitment and Chondrocyte
Differentiation
Noriyuki Tsumaki,* Kazuhiro Tanaka,* Eri Arikawa-Hirasawa,* Takanobu Nakase, Tomoatsu Kimura,§ J. Terrig
Thomas, Takahiro Ochi, Frank P. Luyten, and Yoshihiko Yamada*
Cartilage-derived morphogenetic protein-1
(CDMP-1), a member of the bone
morphogenetic protein family, it has role of in
skeletal formation.
Characterization of bone morphogenetic protein
family members as neurotrophic factors for cultured
sensory neurons
L. M. Farkas, J. Jászai, K. Unsicker and K. Krieglstein Neuroanatomy, University of Heidelberg, Im Neuenheimer
Feld 307, D-69120 Heidelberg, Germany
• The neurotrophic factors may act synergistically in ensuring
neuronal survival.
• The bone morphogenetic proteins have been implicated in
several inductive processes throughout vertebrate
development including nervous system patterning.
• Several bone morphogenetic proteins can be detected in
developing embryonic day 14 rat dorsal root ganglia .
• Growth/differentiation factor-5, bone morphogenetic
protein-2, -4, -7 and -12 significantly increased the survival
promoting effects of neurotrophin-3 and nerve growth
factor on cultured dorsal root ganglion neurons.
Failure of bone morphogenetic protein receptor
trafficking in pulmonary arterial hypertension
Anastasia Sobolewski1, Nung Rudarakanchana1, Paul D. Upton1, Jun Yang1, Trina K. Crilley1, Richard C.
Trembath2 and Nicholas W. Morrell1,*
• Heterozygous germline mutations in the gene encoding the
bone morphogenetic protein type II receptor cause familial
pulmonary arterial hypertension (PAH).
• substitution of cysteine residues in the ligand-binding
domain of this receptor prevents receptor trafficking to the
cell membrane.
• HeLa cells were transiently transfected with BMPR-II wild
type or mutant (C118W) receptor constructs.
Bone Morphogenetic Protein Receptor2 Mutations in
Pulmonary Hypertension
Jane H. Morse Chest 2002;121;50S-53S
Heterozygous mutations in bone morphogenetic
protein receptor (BMPR) 2 cause PPH
Mutations in the Gene Encoding Capillary Morphogenesis
Protein 2 Cause Juvenile Hyaline Fibromatosis and Infantile
Systemic Hyalinosis
Sandra Hanks1,Sarah Adams1,Jenny Douglas1,Laura Arbour2,David J. Atherton3,Sevim Balci7,Harald Bode8,Mary E. Campbell4,Murray
Feingold9,Gökhan Keser10,Wim Kleijer11,Grazia Mancini11,John A. McGrath5,Francesco Muntoni6,Arti Nanda12,M. Dawn Teare13,Matthew
Warman14,F. Michael Pope4,Andrea Superti-Furga15,P. Andrew Futreal16andNazneen Rahman1,,
• Juvenile hyaline fibromatosis (JHF) and
infantile systemic hyalinosis (ISH) are
autosomal recessive conditions characterized
by multiple subcutaneous skin nodules,
gingival hypertrophy, joint contractures, and
hyaline deposition.
Developmental genes:
Two types:
1.maternal effect genes: affects early development through
contributions of gene products from the ovary of the mother
to the developing oocyte.
a) genes regulate anterior-posterior axis pattering:
bicoid –hunchback-caudal-nanos gene.
b) genes regulate dorsal-ventral axis pattering.
dorsal gene (dl).
• Zygotically acting genes: are those in which
gene products contributing to early
development are expressed exclusively in the
zygote.
• For example:
a) segmentation genes
b) homeotic genes.
Maternal effect gene :
• Maternal effects often occur because the
mother supplies particular mRNA to the
oocyte.
• The phenotype is thus determined by the
mother's, rather than the egg's, genotype.
• The oocyte is formed, along with fifteen nurse cells,
from a stem cell.
• The nurse cells secrete maternal mRNAs into the
developing oocyte through a structure known as ring
canal.
OOGENESIS IN DROSOPHILA
Germarium
Germline Cyst Formation
Cystoblast
germline
stem cells
follicle
stem cells
ring canal
Pro-Oocyte
(undergoes
meiosis)
germline: stem cell > cystoblast > 1 oocyte + 15 nurse cells
Class of maternal effect genes:
• Bicoid gene:
key maternal effect gene involved in the formation of
the anterior structure of the egg.
• Bicoid protein diffuse to form a gradient with it’s
highest concentration at the anterior end of the egg
it’s direct the formation of head and thorax.
• It act as transcription activator and translation
repressor.
Nanos genes:
• Key maternal effect gene involved in the formation of
the posterior structures of the embryo.
• Nanos or (nos) protein forms a posterior-anterior
gradient.
• Directs the formation of the abdomen.
• Nanos protein is a translational repressor (direct the
concentration of hunchback mRNAs).
• There are specific microtubule- association
sequences located within the 3’ UTRs of the
mRNA.
• Those sequences are bound by a protein that
can also bind the – ends of the microtubule in
case of bcd mRNA and + end in case of the
nanos mRNA.
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Maturation
Of Drosophila
Oocyte
Movement of bicoid mRNA moves
maternal mRNA toward anterior end
Follicle
cells
Nurse
cells
Anterior
Posterior
Microtubules nanos mRNA moves
toward posterior end
a.
Nucleus
Anterior
Posterior
bicoid
mRNA
b.
nanos
mRNA
Caudal genes & maternal hunchback genes:
• Cad mRNAs and hunchback mRNAs are evenly distributed in
the egg before fertilization because they lack special location
control system.
• CAUDAL protein has a lowest concentration at the anterior
end and highest concentration at the posterior end.
• It activate genes needed for the formation of the posterior
end.
• HUNCHBACK protein has a highest concenyration at the
anterior end and it’s responsible for the formation of the
anterior end.
• Bicoid protein gradient forms at the anterior
end of the egg.
• Nanos protein forms a gradient at the
posterior end.
• The Bicoid protein blocks translation of caudal
mRNA so Caudal protein is made only in the
posterior part of the cell.
• Nanos protein binds to the hunchback mRNA
and blocks its translation in the posterior end.
Control of hunchback mRNA Translation by Nanos Protein:
Three independent Genetic Pathways Interact to Form th
Anterior-Posterior Axis of the Drosophila Embryo
Experiments Demonstrating That the Bicoid Gene Encodes the
Morphogen Responsible for Head Structures in Drosophila
Experiments Demonstrating that the Bicoid Gene Encodes the
Morphogen Responsible for Head Structures in Drosophila
Segmentation genes
• The segmentation genes give 14 parasegments that are
closely related to the final anatomical segments.
• Mutations in segmentation genes alter the number of
segments or the internal organization.
• Gap Genes
• Pair-rule Genes
• Segment Polarity Genes
Gap genes
• The gap genes are the first of a cascade of the segmentation
control genes.
• These genes map out the basic subdivisions along the anteriorposterior axis. establish broad regional domains of body plan of
the embryo each of which covers areas that will later develop into
several distinct segments.
• All encode transcriptional factors.
• Mutation in gab genes results in the deletion
of regions consisting of several adjusting
segments.
• The gradients of Maternal effect (Bicoid, and Caudal)
work as transcriptional regulation (activators/
repressor) for Gap gene expression.
• Bicoid activates Kruppel and hunchback and others;
their proteins spread and activate pair-rule genes,
etc. Sequential subdivision strategy.
• The resultant proteins from these genes become
stabilized and maintained by interactions between
the different gap genes themselves.
• activity is characterized by low levels of
transcriptional activity across the entire
embryo, with discreet areas of high activity
forming as cleavage continues.
• Transcription patterns of anterior gap genes are inititated by the
different concentrations of Hunchback and Bicoid.
• in the anterior of the embryo high Hunchback leads to the
transcription of Giant.
• lower Hunchback leads to the transcription of Krüppel represses
posterior expression Giant and Knirps .
• knirps inhibits hunchback transcription, thereby setting
the posterior boundary of Hunchback.
• Caudal protein which is highest gradient in the posterior
portion of the embryo activate knirps and giant.
Gt: gaint
Hb: hunchback
Kr: kruppl
Kni: knirp
pair-rule genes
• pair-rule genes expression leads to division of the
embryo into number of regions, each of which
contains a pair of parasegments. cover up a pattern of
7 repeats vertical to the anterior-posterior axis, then
subdivide to 14 repeats.
• All encode transcriptional factors. They are controlled
directly by the gap gene proteins, which activate the
transcription of some pair-rule genes while repressing
the transcription of others.
• Mutations result in embryo with half the
normal segment number either odd- or evennumbered stripes.
• Mutant at fushi-tarazu gene
• gap genes initiate the expression of members of the
pair-rule class )even-skipped, hairy ,and runt(
primary" pair-rule genes.
• Interactions between primary pair-rule genes
become self-stabilized once inititated, and they are
responsible for activation or inhibiting the secondary
pair-rule genes.
• Pair-rule and gap genes also interact to regulate the
homeotic genes that determine the identity of each
segment.
• Interestingly, although the pair-rule genes
were identified genetically by their pattern
defects in alternate segments, this class of
segmentation genes is expressed in a wide
variety of tissues during embryogenesis.
• pair-rule genes are expressed in the
mesoderm, gut and most notably the central
nervous system .
polarity genes
• set the anterior-posterior axis of each segment that will
become the segments seen in the larva and adults and
responsible for maintaining certain repeating structures
within the segments.
• Mutations produce embryos with the normal segment
number, but with part of each segment replaced by a mirrorimage.
• The majority are transcriptional factor but are also signaling
protein as hedgehog.
• This expression pattern is initiated by the pair-rule genes (like
even-skipped) that code for transcription factors that regulate
the other genes.
• Mutations results in segments replaced by mirror images .
• Many segment polarity genes encode proteins
that are part of the Hedgehog and Wnt cellsignalling pathways (ligands, transmembrane
proteins, receptors, signal transducers,
transcription factors).
Homeotic genes
 The final stage of specification of segment body plan is established
by activation of genes called homeotic selector genes
 These genes are responsible for controlling the developmental
program that that determine the final cell fat decision of each
segments
 The importance of their function is obviously clear in their mutant
phenotype
Homeotic genes
 Homeo refer to transformation of one structure or segment to
another.
 There are 8 genes identified as homeotic selector gene
 Each one code for transcription factor that contain DNA binding
motif (hoeodomain)
 The 8 genes are collectively organized in a complex known as
Hom-c
Homeotic genes
 Where they are divided into 2 groups:
 ANTENNEPEDIA complex which include :
 Antennapedia (Antp)
 Labial (lab)
 Proboscidea (pb)
 Deformed (dfd)
 Sex combs (scr)
 The genes of this cmplex involved in the specification of head
and thoracic segment.
Homeotic genes
 The bithorax complex which involve:
abdominal-B
ultrabithorax
abdominal-A
abdominal-B
Which are involved in the specification of abdominal
segment identities.
There is a striking correlation between the organization of
the homeotic selector genes within the fly genome and their
transcription expression domains along A-P axis of the
embryo and the adult fly.
The linear arrangement of the genes in the HOM-C
complex correlate precisely with their expression along the
A-P axis.
Homeotic genes
 The expression of the homeotic genes require in put from gab
genes and pair-rule genes that control their expression within
parasegmental domain.
 Gap and pair-rule protein act through cis- acting regulatory region
(initiator enhancer elements to their activator or repress homeotic
gene expression.
 For example the graidient of Hunchback and Krupple negatively
regulate the expression of abdA, abd B in the head and thorcic
segment.
 Another control mechanism : as transcription factor the protein the
protein coded by the homeotic selector gene act to regulate the
expression of each other.
Homeotic genes
 For example the expression of Antennapidia complex is repressed
by the combined activity of the bithorx complex protein.
 The absence of Ubx cause the posterior part of the Antennapidia to
expand into a region normally express ubx.
 The homeotic selector genes are required for segment identity
during larval and adult stage , their for another mechanism are
needed because their regulation (gab,pair-rule) during embryo is
transient
 How do the drosophilla maintain their homeotic genea expression
during late stage?
Homeotic genes
 The modification of chromatin structre play a major role in their
controlling mechanism in adult which is carried out by two classes
of genes:
 Polycomb group:
 This group inactivate the cis-regulatory region that control
homeotic gene expression ,by remodeling chromatin structure into
more compact states threr by inhibit their transcription during
subsequent stages.
 Trithorax group:
 There are protein appear to act collectively to keep chromatin in a
state that favors transcriptional activation.
Homeotic genes
 Homeotic genes are responsible for regulating the specific genetic
program that direct cells within each segments toward their final
cell fats?
 Their expression is not restricted to an individual segment , most
are expressed in broader pattern along the A-P axis
 All homeotic selector genes share highly conserved DNA-binding
domain. ?
 This contribute to weak binding specificity for an individual
homeotic genes to a particular region than other.?
 They depend on cofasctor proteins modulsate their activity in a
context- dependent manner