Ear development

Question 1

What makes up the outer ear and where does it run to?

Answer 1

• Pinna: visible structures at each side of the head, responsible of funnelling sound into the ear canal.
• The ear canal, up to the timpanus, is also part of the outer ear structures.

Question 2

Where is the middle ear?

Answer 2

• Air filled cavity, encased in the temporal bone of the skull.

Question 3

What are the 3 bones of the middle ear?

What do these bones do?

Answer 3

maellus, incus and stapes

They form a chain physically connecting the timpanus and the oval shaped opening that transmits sound waves into the inner ear.

Question 4

How are sound waves transmitted to the inner ear?

Answer 4

• The vibration of the timpanus moves the ossicles, and the membrane in the inner ear opening vibrates with ossicle’s movement transmitting the sound waves into the inner ear

Question 5

What are the two functions of the inner ear?

Answer 5

• This is the compartment morphologically most complex. It has two functions: sound perception and balance.

Question 6

Where are sound waves in the inner ear perceived?

Answer 6

• Sound perception occurs in the cochlea, where sound waves are transformed into electrochemical stimuli.

Question 7

How does the ear detect balance?

Answer 7

• Balance is modulated by the dorsal structure in the inner ear, called the vestibule. Three semicircular canals project in the three cardinal axes and are filled with fluid that moves with head movement. This fluid movement is detected at the base of the canals by bundles of sensory cells organised in structures called the crista.

Question 8

What is the external and middle structure of the ear derived from?

Answer 8

The external and middle structures of the ear are assembled from ectodermal, mesodermal and neural crest derivatives from the first and second pharyngeal arches -

Question 9

What are the ossicles derived from?

Answer 9

The ossicles derive from first and second pharyngeal neural crest cells, which undergo endochondral ossification.

Question 10

What is the inner ear and associated neurones derived from?

Answer 10

The inner ear and all the associated neurons derive from the otic placode.

Question 11

What is the inner ear divided into?

Answer 11

• The inner ear is divided into the dorsal segment and the ventral segment

Question 12

What is the dorsal segment of the inner ear called and do?

What is at the apical surface of the hair cells found in the vestibule?

Answer 12

• The dorsal segment is called the vestibule is involved in balance, detecting movement and acceleration. It is formed by three canals which contains fluid, this moves when we move and change speed. This movement of fluid is detected by sensory organs that are located at the base of these semi-circular canals. The sensory neurones consist of groups of specialised cells that are called hair cells.
• At the apical surface of hair cells we can see a bundle of stereocilia projecting. This cilia is coupled to each other and are very rigid structure. They become deflected by the movement of the fluid of the semi-circular canals. This movement leads to ion influx within the hair cells which triggers neurotransmitter release and nerve impulses

Question 13

What does the ventral segment of the inner ear consist of?

What is the organ of corti?

Answer 13

• The ventral segment of the inner ear is the cochlea that is involved in detecting sound. There is an important structure in the cochlea called the organ of corti that runs along the cochlea. The organ of corti is located on one of the walls within the spiral of the cochlea and runs along it, which is formed by hair cells that are able to detect sound

Question 14

What is the organ of corti?

Answer 14

The Organ of Corti is an organ of the inner ear located within the cochlea which contributes to audition.

Question 15

What are the 2 cell types in the organ of corti?

Answer 15

Organised into two regions: the inner hair cells row is surrounded by supporting cells and the outer hair cells which consist of three rows of hair cells (they are very stereotypic supported by other cells).

Question 16

What do the inner hair cells do?

Answer 16

• Connected to auditory nerve fibres. The inner hair cells are the first cells to detect the sound waves and the outer cells mainly function to amplify these sound waves and a bigger array of sounds.

Question 17

What frequency of sound do hair cells detect in the ar

Answer 17

Cells that detect the lowest frequencies are the hair cells at the apex of the cochlea.

Question 18

Why as we get older lose the ability to hear high frequency noises?

Answer 18

• As we get older we lose the ability to hear high sound frequencies because the hair cells located at the base of the cochlea are first encountering sound waves and therefore more exposed to the damaging effect of sound.

Question 19

Recap: what does the inner ear come from?

What is the otic placode?

Answer 19

• The ear and its structures come from the:
• The otic placode is a thickening of the head ectoderm that flanks the hindbrain between rhombomere 5 and 6.
• This thickening starts to invaginate over itself.

Question 20

What are the different placodes and what do they do?

Answer 20

There are several placodes in the developing embryo such as the olfactory placode, lens placode, trigeminal, optic and epibrachial placode. These will all form neurones that will detect different sensory inputs.

Question 21

Where do all the different placodes originate form?

Answer 21

All of these placodes derive from a region in the embryo called the Pan Placodal domain. This is a thin row of ectoderm that surrounds the neural plate (this is different to the neural crest).

Question 22

What signals inhibit and form the pre-placodal region?

What domain forms the otic and epibrachial placodes?

What forms the olfactory, lens and trigeminal placodes?

Answer 22

• Wnts secreted by the neural plate, and BMPs secreted by the epidermis, suppress PPR fate.
• Cerberus (a BMP/Wnt antagonist) and Fgf, secreted by the mesoderm underlying the PPR domain, induce PPR fate.

The PPR is patterned in the AP axis:
• Otic and epibranchial placodes derive from a Gbx2 positive domain
• Anterior placodes derive from a Otx1 positive domain: olfactory, lens and trigeminal placodes

Question 23

How do the otic and epibrachial placodes form?

What gene is expressed in the OEPD?

Answer 23

• These placodes appear in the gbx2 positive domain, which is at the level of the hindbrain
• Initially there will be a broad domain called the OEPD, which is specified as future placodal tissue, which will be subdivided into a dorsal and medial domain called the OP and Epi
• One characteristic gene that becomes expressed in the OEPD is Pax2.
• Pax2 becomes restricted to the otic vesicle in particular

Question 24

Describe the signals that form the otic and epibrachial placode

Answer 24

• Here we have a cross section where we can see the neural tube, on the left we can see the posterior PPR and on the right a segregation has occurred
• The posterior PPR is induced by FGFs from the underlying mesoderm
• Wnt8a and FGFs from the hindbrain promote otic placode formation
• Wnt8a suppresses epibranchial placode formation
• Epibranchial fate is induced by Fgfs and Bmps from the pharyngeal endoderm

A – endodermal tissue of the pharyngeal arches is a source of fgf8 that will induce fgfs in the mesoderm.
B – fgfs in the mesoderm will induce Wnts and Fgfs in the hindbrain as the neural plate folds to give rise to the neural tube. In addition, they promote the formation of the posterior PPR from the non-neural ectoderm
C – Wnts and fgfs from the neural tube will induce otic placode fate in the PPR.
D – Wnt will also repress the epibranchial cell fate, so it cannot occur in the PRR. Epibranchial fate also requires induction by fgs and BMPs.
E – so we have FGFs inducing otic region and FGFs and BMPs inducing epibranchial placodes

Question 25

What will the otic cup do once it is specified?

Answer 25

• Once the otic cup is specified it will invaginate and will bud from the overlaying ectoderm to give rise to the cysts underneath the ectoderm, next to the forming neural tube.
• The otocyst is the primordium from which all the components of the inner ear will derive including the neurones that innervate the sensory organs in the vesicle and in the organ of corti

Question 26

Describe the morphogenesis of the otic vesicle

Answer 26

• The otic vesicle will undergo a complex process of morphogenesis to give rise to an intricate structure.
• The different regions of the otic vesicle will start budding off and will form each one of the structures which will form the inner ear.
• The semicircular canals derive from the dorsal portion of the otic vesicle while the Cochlea will derive from the ventral bud that will grow and coil over itself.

Question 27

How is the optic vesicle specified to form different regions of the inner ear?

Answer 27

• The vesicle will come patterned by the expression of several different transcriptions factors within the otic vesicle that drive the formation of different regions of the inner ear.
• This forms the 3 axis.
• We can see this below:

This all leads to combinatorial expression patterns that defines different quadrants of the developing ostocyst

Question 28

What happens if we lose some the expression of some TFs in the otic vesicle?

Answer 28

• The quadrants give rise to specific structures in such a way that if we remove the expression of one of those transcription factors we can lose an entire inner ear structures
• For example if we lose Pax2 expression in the ventral half of the otic vesicle, we lose all the ventral structures that will form
• For example if we lose Dlx5 expression all of the dorsal structures are lost
• Same goes for Otx1 and Hmx3

Question 29

How is the AP and DV axis in the otic vesicle patterned?

Answer 29

• The factors that pattern the developing embryo also pattern the otic vesicle
• For example along the AP axis we know there is a gradient of RA along the hindbrain, a gradient of fgf. These two gradients are important to establish anterior genes in the otic vesicle
• Same goes for DV axis patterning

Question 30

What does Sox2 and lmx1a do?

Answer 30

• The prosensory domains are defined by expression of the transcription factor Sox2
• Sox2 is expressed in a broad initial domain (ventro-anteromedial) of the otocyst
• Lmx1a defines non-sensory territories

Question 31

What is the region called that expresses Sox2 and what does it form?

What does a Sox2 knockout cause?

Answer 31

The domain that expresses Sox2 early on is called a pansensory region, a region of the otic vesicle that is competent to give rise to the sensory organs

The prosensory patches become specified that come from the pansensory domain

• Sensory precursors are absent
• Both hair cells and supporting cells are absent

Question 32

How do cells of the cochlea exit the cell cycle and differentiate?

Answer 32

• The Sox2 positive domain runs along the Cochlea, as development progresses the Sox2 positive cells exit the cell cycle and differentiate to give rise to the hair and support cells in this particular region.

• Cell cycle exit is promoted by p27Kip1, a molecule that is a regulator of the cell cycle
• The cell cycle negative regulator p27Kip1 is upregulated in a wave, from the apex to the base
• p27Kip1 blocks the transition from G1 to the S phase in the cell cycle

Question 33

What does p27Kip1 mutants (have delayed cell cycle exit) cause?

Answer 33

• This means that cells in the prosensory domain will continue to proliferate for longer.
• So more hair and support cells differentiate

Question 34

Differentiating cells start expressing atoh1

Answer 34

• As cells exit the cell cycle and start differentiating, they also start expressing atoh1. This is a transcription factors, a proneural gene, important to specify the hair cells
• Expression of atoh1 starts at the base and progresses towards the apex
• Cells differentiate from base to apex – the last ones to exit the cell cycle are the first ones to differentiate
• Differentiating cells start expressing the proneural transcription factor Atoh1

Question 35

How is the regular pattern of hair cells/support cells established?

Answer 35

This regular array is due to lateral inhibition