Translational Regulation of Development

SYED MUHAMMAD KHAN (BS HONS. ZOOLOGY)
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Translational Regulation of
Development
Once the RNA has reached the cytoplasm, there is still no guarantee that it will be
translated. The control of gene expression at the level of translation can occur by many
means; some of the most important of these are:
 Differential mRNA longevity
 Selective Inhibition of mRNA translation (Stored oocyte mRNAs)
 micro-RNAs
 Control of RNA expression by cytoplasmic localization
 Stored mRNAs in brain cells
Differential mRNA Longlivety
The longer an mRNA persists, the more protein can be translated from it. The stability of
a message often depends on the length of its polyA tail (After transcription, a poly-
Adenine tail is attached at the 3’ end of RNA; it is a part of post-transcriptional
processing).
In some cases, messenger RNAs are selectively stabilized at specific times in specific
cells. In female rats, casein (milk protein) mRNA is normally short-lived. But when the
rat is lactating (feeding milk to babies), prolactin is released. Prolactin increases the life
of casein mRNA.
Selective Inhibition of mRNA Translation – Stored oocyte mRNAs
The oocyte (precursor of ovum) often makes and stores mRNAs that will be used only
after fertilization occurs. These messages stay in a dormant state (inactivated) until they
are activated by ion signals that spread through the egg during ovulation or fertilization.
These stored mRNAs encode proteins that:

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1. Are needed during cleavage.
2. Regulate the timing of early cell division.
3. Determine the fates of cells. These include the bicoid, caudal, nanos, etc. in
Drosophila.
mRNAs are supposed to be available for translation. Therefore, there must be inhibitors
preventing the translation of these mRNAs in the oocyte, and these inhibitors must
somehow be removed at the appropriate times around fertilization, i.e. before
fertilization, inhibitors such as Maskin inhibit translation of mRNA, but upon fertilization,
Maskin (inhibitor) is displaced by an enzyme, translation can then proceed.
Figure: Translational regulation in oocytes. Messenger RNAs are often found as
circles, where the 5' end and the 3' end contact one another. (Left) The 3' and 5' ends
of the mRNA are brought together by maskin, a protein that blocks the initiation of
translation. (Right) During ovulation, maskin is displaced and translation of mRNA can
now initiate.
The 5' cap and the 3' untranslated region (UTR) seem especially important in regulating
the accessibility of mRNA to ribosomes. If the 5' cap is not made or if the 3' UTR lacks a
polyA tail, the message will not be translated. The oocytes of many species use these
ends to regulate the translation of their mRNAs.

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Micro-RNAs
MicroRNAs (miRNAs) are RNAs of about 22 nucleotides and are made from longer
precursors, they inhibit translation in a target mRNA.
1. Synthesis of miRNA:
The miRNA gene encodes a pri-miRNA (primary micro RNA) that has several hairpin
regions. The pri-miRNA is processed into individual pre-miRNA "hairpins" by an
RNAase enzyme. These pre-miRNA hairpins are exported from the nucleus to the
cytoplasm. Once in the cytoplasm, another RNAase separates the single-stranded
miRNA.
2. RNA-Induced Silencing Complex:
The strand (of miRNA) is packaged with proteins to form the RNA-induced silencing
complex (RISC). RISC binds with target RNA to inhibit translation.
3. Working of RISC:
The miRNA complex (RISC) can inhibit
translation by:
a) Blocking binding of RNA with ribosomes
or initiation factors.
b) Recruiting endonucleases to digest poly-A
tail of target RNA, this will destroy it.
c) Recruiting proteases to destroy nascent
(in process) protein.
Formation and use of microRNAs: (1) The
miRNA gene encodes a pri-miRNA (primary
micro RNA) that often has several hairpin
regions. (2) The pri-miRNA is processed into

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individual pre-miRNA "hairpins" by an RNAase enzyme, and these are exported from
the nucleus. (3) Once in the cytoplasm, another RNAase separates the strands of the
double-stranded miRNA. (4) One strand is packaged with proteins into the RNA-
induced silencing complex (RISC), which binds to the target RNA to inhibit translation.
Figure: The miRNA complex can block translation by: (A) blocking the binding of the
mRNA to initiation factors or ribosomes; (B) recruiting endonucleases to digest the
polyA tail of the mRNA, thereby causing its destruction; and (C) recruiting protein-
digesting enzymes that destroy the nascent (under process) protein.
Control of RNA Expression by Cytoplasmic Localization
A majority of mRNAs (about 70% in Drosophila embryos) are localized to specific
places in the cell (they are either found in only one region and not any other or their
concentration is not the same in every region). There are three major mechanisms for
the localization of an mRNA:
(1) Diffusion and local anchoring:
Messenger RNAs such as nanos (in Drosophila) diffuse freely in the cytoplasm.
However, when they diffuse to the posterior pole of the Drosophila oocyte, they are

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trapped there by proteins that reside particularly in these regions. These proteins also
activate the mRNA, allowing it to be translated.
Figure: The nanos (mRNA), produced in Drosophila oocyte, are free to roam around the
cytoplasm, but when they reach the posterior end, they are anchored and their
translation is initiated.
(2) Localized protection:
In this case, the mRNAs are free to roam the cytoplasm (just like the first case) but they
are degraded or digested (or their proteins are digested) in all regions except one,
where they are protected, i.e. localized protection (an example is hsp83 – heat shock
protein mRNA in Drosophila).
Figure: The hsp83 mRNA is degraded in all regions of the Drosophila embryo except
the posterior region where it is offered protection.

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(3) Active transport along the cytoskeleton:
In this case, the mRNA is recognized by proteins that can bind these messages to
"motor proteins" that travel along the cytoskeleton to their final destination. These motor
proteins are usually ATPases that split ATP for their motive force. For instance, in
Drosophila oocytes, the bicoid messages (which instruct the formation of the head) are
localized to one end of the oocyte via the cytoskeleton.
Figure: In Drosophila oocyte, bicoids (mRNAs) are transported to the anterior portion by
the cytoskeleton.
Stored mRNAs in Brain Cells
The storage of long-term memory, in the brain, requires new protein synthesis, and the
local translation of mRNAs in the dendrites of brain neurons increases the strength of
synaptic connections. Several mRNAs are transported along the cytoskeleton to the
dendrites of neurons. These messages include those mRNAs encoding:
1. Receptors for neurotransmitters (needed to transmit the signals from one neuron to
another)
2. Activity-regulated enzymes
3. Cytoskeletal components are needed to build a synapse.

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One of the proteins responsible for constructing specific synapses is brain-derived
neurotrophic factor, or BDNF. BDNF regulates neural activity and is critical for new
synapse formation. BDNF induces the local translation of these neural messages
(mentioned above) in the dendrites.
Post-translational Regulation of Gene Expression
Once a protein is made, it may become part of the structural framework of the cell, or it
may become involved in one of the many enzymatic pathways for the synthesis or
breakdown of cellular metabolites. Several changes can take place in a protein even
after translation:
1. Cleavage of inhibitory sections (to activate protein).
2. Transporting proteins to their required location (where they have to function).
3. Assembling with other proteins (i.e. Haemoglobin consists of 4 peptide chains).
4. Attachment of cofactor (i.e. ions like Ca2+, other metal ions, phosphate groups,
acetate groups, etc.)

Translational Regulation of Development

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