9. homeotic genes- molecular architects

8/10/2019 9. Homeotic Genes- Molecular Architects

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LECTURE- 10

PART- I CYTOGENETICS
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HOMEOBOX GENESTHE

MOLECULAR ARCHITECTS
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Homeobox genesArchitects of body plan

How does a single fertilized cell develops into a complex

organism like a fly, a mouse, or a human being?

Von Baer in the early 19th century observed that all vertebrates look

very similar in their early stages of embryonic development.

Geoffroy Saint-Hilaire remarked that all animals have the same body

plan. As the main nerve cord is in the front part of insects and in the

back part of vertebrates, he hypothesized that vertebrates are

essentially upside-down invertebrates!


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Homeobox genesArchitects of body plan

Homeoticgenes(homeo = alike) or homeobox genes

are similar in structure and function in all animals.

They are an important class of regulatory genes.

They serve as molecular architects and direct the

building of body segments according to definite detailed

plans.


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Homeobox genesWhat are they?

The genes are tandemly repeated to form a homeobox

gene family.

They code for proteins that bind to DNA; have a homeobox

sequence- conserved DNA motif of about 180 base pairs.

Their proteins contain a homeodomain(DNA binding

domain- 60 amino acids long), and a variable domain.


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Homeobox genes produce DNA-binding

proteins

The homeodomain

contains a helix-turn-

helix DNA-binding motif

characteristic of many

DNA-binding proteins.


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Role Homeobox genes

Homeobox genes and their encoded homeodomain proteins

play important roles in the developmental processesof

multicellular organisms.

They play crucial roles from the earliest steps in

embryogenesis such as cell differentiationand

organization within segments:

- e.g. the differentiation of neurons in the nematode

(Caenorhabditis elegans).


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Mechanism of function of Homeobox genes

The homeobox genes can be thought of as genetic

switches ormaster control genesthat turn different

programs of cellular differentiation on or off.

Homeobox proteins are transcription factorsthat

upregulatethe transcription of other genes by binding to

their upstream elements.


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Mechanism of function of Homeobox genes


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Order of development of multicellular organisms

Polarity- formation of the axis by which embryo differentiates.

Before fertilization an egg has a gradient of proteins that help

to establish its polarity (anterior- head and posterior- tail).

After fertilization Maternal Effect genes reinforce polarity and

also establish the dorsal (back) and ventral (belly) orientation.

Segmentation occurs driven by Gap genes, Pair rule Genes

and Segmentation polarity genes.

Finally the homeotic genes are switched on.


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Order of development in Drosophila

Gap genes

Establishes domains of distinct identity along the anterior-posterior axis.

The gap domains are multiple segments in width.

Pair-rule and segment polarity genes

These genes merely subdivide the embryo into parasegmentsand organize short-range pattern within a parasegment

Homeotic genesHomeotic genes assign distinct identities to differentparasegments, by initiating preprogrammed differentiation of

each segment.
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Regulation of Drosophilahomeotic gene complex

Homeotic genes interact with a variety of information from

the gap, pair-rule, and segment polarity genes.

Mutations in pair-rule genes have also been shown to affect

homeotic gene expression

Cross-regulation between homeotic genes: homeotic genes

also regulate each other.

Cross-regulatory interactions are important in defining the domains ofexpression.

More posterior acting genes function as negative regulators of their

more anterior neighbors.


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The homeotic genes in Drosophila

The activities of a number of homeotic genes are required to establish

the identity of parasegments in the trunk region (posterior head, thorax,

and abdomen) of the embryo.

These genes are clustered in two major groups called the:

Antennapediacomplex (ANT-C)- responsible for segmental

identity in the head and anterior thorax

AND

Bithoraxcomplex (BX-C)- responsible for segmental identity in

the posterior thorax and abdomen.


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The five Drosophilagenes that belong to the ANT-C are:

- Labial (lab)

- Proboscipedia (pb)

- Deformed (Dfd)

- Sex combs reduced (Scr)

-Antennapedia (Antp)
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The three Drosophilagenes that belong to the BX-C are:

- Ultrabithorax (Ubx)

- Abdominal-A (Abd-A)

- Abdominal-B (Abd-B)

Within the ANT-C and BX-C, the order of the genes on the

chromosome is the same as the order of segments that they

affect along the embryonic axis.

This is referred to as the "colinearity principle".


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Colinearity principle

The homeobox gene family comprises a cluster of genes that encodes a specific body

part. The posterior ones regulate the anterior ones.


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ANT-C homeotic gene mutation of Drosophila

ANTP controls development of middle segment of the thorax

(mesothorax) of Drosophila.

Mesothorax produces a pair of legs that are distinct from the forelegsand hindlegs.

ANTP encodes a homeodomain regulatory protein that is expressed in

the mesothorax during embryo development.

But a dominant ANTP mutation caused by a chromosome inversion,

brings ANTP protein-coding sequence under the control of regulatory

DNA that mediates gene expression in the head tissues.


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ANT-C homeotic gene mutation of Drosophila

This mutation results in legs developing instead of antennae in the

head region.

Hence mutations in an ANT-C gene result in gross organizationalchanges.


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Bithorax complex (BX-C)

UBX (ultrabithorax) encodes a homeodomain regulatory

protein that controls the development of the 3rdthoracic

segment (metathorax).

UBX represses genes responsible for the development of the

2ndthoracic segment (mesothorax).

UBX regulatesANTP; represses ANTP expression in the

metathorax and restricts its expression to mesothorax only.
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UBX mutants cannot regulate ANTP expression.

This results in ANTP also being expressed in the metathorax

and transforming it into a second mesothorax.

Mesothorax has a pair of legs and wings; while metathorax

has a pair of legs and halteres (balance flies during flight)

UBX mutants have 2 pairs of wings!!!


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A mutation called CBX (contrabithorax) causes UBX to be

expressed in the mesothorax.

CBX mutants look like wingless ants.


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Vertebrate Hox genes

In vertebrates HOX genes are found in gene clusters on

the chromosomes. Mammals have 4 Hox clusters

(Hoxa, Hoxb, Hoxc, Hoxd), organized into thirteen

homology groups.

Mice and humans contain 38 Hox genes arranged in

these 4 clusters.


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Vertebrate Hox genes- human
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Vertebrate Hox genes- mouse


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Vertebrate Hox genes- mouse and human- same


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The Vertebrate Hox Gene Complex

Only about 38 genesout of a total of about 30,000 control

most of the development, architecture, and appearance of

the body plan of complex mammalian species.

The mouse Hox complex is exactly similar to the human

Hox complex.


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The Vertebrate Hox Gene Complex

The organization of the genes in each cluster reflects its

anterior-posterior expressionin the body plan (spatial

colinearity).

Unlike in Drosophila, vertebrate Hox genes are also

temporally colinearin addition to being spatially colinear.

Homeotic genes are expressed within segmented and

unsegmented structures within the body plan.


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Mutations in human Hox genes

Human Hox gene mutations

have shown to affect limb

development.

A mutation in the human

Hoxd13gene results in

polydactyly.

Mutation in Hox gene can also

result in an extra rib.
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The Hox genes and the evolution of the eye

Swiss biologist, Walter Gehring and his team, found that the

Hox gene responsible for induction of the Drosophilaeye is

virtually identical to the one that induces the mouse eye.

This Hox gene switches on eye formation in the myriad of

creatures that see. Hence, it appears that all eyes, no

matter how differently constructed they appear now, had a

common evolutionary origin.


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Homeobox genes have a wide phylogenetic

distribution

Homeobox genes have a wide phylogenetic distribution-

found in baker's yeast, plants, and all animal phyla that

have been examined so far.

The incredible conservation of genes across species

suggests that the homeobox gene clusters and their role

in development are of ancient origin.


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distribution

All invertebrates and vertebrates came from a bilateral

ancestor with 7 Hox genes that lived 600 million years ago.

In insects, a gene near the right end of the cluster was

duplicated.

In vertebrates, the entire Hox cluster was duplicated:

3 times in mammals up to 8 times in some types of fish.

The duplicate genes were then free to take on new functions,

often leading to more-complex body structures.


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1 billion years ago

600 million years ago


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distribution

The differences in homeobox gene clusters that areseen between species only occur with respect to the

number of clustersas well as to the number of genes

involved in each cluster.

H b h id h l ti


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distribution

Hence, Flies and people are just variations on a theme of how to

build a body planthat was laid down in some worm-like creature

in the Cambrian period."

If a gene plays a central role in development in the fly, it is worth

determining whether it plays a similar role in another organism.

Comparing genes by sequence homology have proved extremely

successful in elucidating the role and identity of several human

homeobox genes

9. homeotic genes- molecular architects

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