BIOS1165 - Embryology

what are the 4 processes required for normal embryonic development?

Proliferation = ability of a cell to divide which allows for multi-celled organisms

Differentiation = process of turning from one cell type → another e.g early unspecialised embryo → specialised cell

Interaction = between similar / different cell types

Movement = movement of the different processes

what are concepts that help with the molecular regulation of cell identity?

• gene expression

• protein expression

• microRNA

• epigenetics

what signalings are involved in regulating cell identity?

• Autocrine signaling = cell itself secretes molecules that act back onto itself (local effect)

• Paracrine Signaling = one cell secretes a factor → acts on a nearby cell = changes its function / identity (local effect)

• Hormonal Signaling = occurs further away, secreted from one area and can affect another area

whats a morphogen?

small molecule (protein) / ligand >> binds to receptor >> downstream signalling >> create a cellular response

• Could also act as an inhibitor = no downstream signalling

what. are morphogen gradients?

the morphogen gradient = tells the cell how to behave

in a blastocyst, what process forms it and what does it consist of?

Formed by process called compaction

Consists: 

• outer trophectoderm cell layer = creates the placenta

• Inner cell mass = creates embryo

• Zona Pellucida = protects embryo

what are the 2 main steps that occur in post implantation development?

1. Trophectoderm cells bury into the uterine lining = trophoblast

   1. The more cells we have, the more hcG is produced > required for placental development

2. Embryo has to adhere, attach, invade the lining (D8-9)

   1. Hypoblast = forms the yolk sac = provides nutrients to embryo before placenta

   2. Epiblast = further differentiates into all cells of the body

   3. Amniotic Cavity = where the amniotic fluid fills in

what is gastrulation and the 3 main steps?

forms the definitive germ layers

1. Forms the primitive streak > gets longer over time (~1.5mm)

2. The primitive ectoderm cells undergo gastrulation 

3. Forms the 3 Definitive Germ Layers which will form parts of the body

what 3 layers does the primitive ectoderm form? and what are these 3 definitive germ layers forming?

what are these areas called?

what is the oropharyngeal membrane? prechordal plate? neural plate? notochord? primitive node? primitive streak? cloacal membrane?

oropharyngeal membrane = forms mouth

prechordal plate: organising centre = influences for brain // forms the head, face, pharyngeal

neural plate: formed by thickening of definitive ectoderm = forms the CNS

notochord: from the mesoderm, will send signals to specialised spinal cord and influences the neural plate // forms vertebral discs

primitive node = end of primitive streak

cloacal membrane = forms the anus

what is neurulation and its steps?

formation of the nervous system

1. Neurulation requires morphogen signals from organisers (prechordal plate, notochord)

   

2. Neural plate derived from definitive ectoderm > ready to undergo neurulation by day 19

3. Neural Tube Formation

what are the patterning of brain key parts?

primary brain vesicles (3-5 wk) = forms neural tube etc

secondary brain vesicles (5wk) = forms cerebrum, spinal cord etc.

how does the patternign of the spainal cord occur?

what are neural crest cells? cranial neural crest cells? neural tube?

• Neural crest cells — come from dorsal end of neural tube—migrates→ mesenchymal cells
  
  

• Cranial neural crest cells (subtype): originate from the cranial end of the neural tube = migrates to pharyngeal arches→ bones, cartilage, connective tissue of face, teeth, peripheral neurons, glia of cranial nerves

• neural tube = cells have tight connections = NOT migratory

  • a hollow embryonic structure that develops into the central nervous system, including the brain and spinal cord.

what is somitogenesis?

forming somites

• Derived from: paraxial mesoderm 

• Somites = → blocks of mesoderm (that forms middle structures: blood, muscles, cartilage, bone…)

  • 38 pairs: cranial, occipital, cervical, thoracic, lumbar, sacral, coccygeal regions

  • Partially give rise to some vertebrae

• Forms: axial skeleton (ribs / vertebrae) - bone and cartilage // skeletal muscle

  

label 4 wk embryo with its somites:

what are pharyngeal arches?

Five paired, bilateral (on both sides) embryonic structures

• It counts 1,2,3,4,6 → the 5th one disappears / doesn’t develop for humans

• Located on: lateral surface of developing neck / head

• Appears as “bulges”

Forms: structures of the face, nasal cavity, mouth, larynx, pharynx, neck

• Bone / cartilage

• Muscle / connective tissue 

• Nerves

• Glands

what does the neural crest cells form?

forms the PNS which includes the cranial nerves

what pharyngeal pouches create what?

pouch 1 = middle ear / eustachian tube

pouch 2 = tonsils

pouch 3+4 = parathyroid glands + thymus

what is pharyngeal arch 1 involved in?

muscles of mastication / trigeminal nerve / hearing bones + cartilage

what is pharyngeal arch 2 involved in?

facial expression muscles / facial nerves / anchorage

what is pharyngeal arch 3 involved in?

inspiration muscles, glossopharyngeal nerve, swallowing + speech bones / cartilage

what is pharyngeal arch 4 + 6 involved in?

sound + swallowing muscles / vagus nerve / voice control /+ airway support

what are the nasal septum / nasal alae / nasal bridge / philtrum / upper lip / lower lip formed by?

what is: spina bifida, anecephaly, celft lip, cleft palate

Spina Bifida	Anencephaly
= improper caudal closure of the neural tube	= improper cranial closure of neural tube

Facial Clefts

incomplete fusion of facial structure during development

Cleft Lip:	Cleft Palate:
Failure of fusion between lateral or medial nasal processes and the maxillary process	Failure of fusion between the primary palate and palatal shelves
Surgery: 2-3 months post birth	9-18 months post birth

Cleft Palate

Primary Palate	Secondary Palate
Failure of fusion of the primary palate with the palatal shelves.  Occurs anterior to the incisive foramen	Failure of fusion of the primary palate with the palatal shelves Occurs posterior to the incisive foramen Often involves hard and soft palate

what are submucous clefts? macrostomia?

Submucous Clefts

• Involves hard / soft palate

• Appears intact, but there are deficits in bone + muscle

Macrostomia

Large mouth → failure of the maxillary and mandibular processes to form

what pharyngeal arches are responsible for what parts of the tongue?

• 1st Pharyngeal Arch = responsible for anterior ⅔

• 2nd, 3rd, 4th Pharyngeal Arch = responsible for posterior ⅓ 

explain the timeline of tongue development:

1. Week 4:  the lateral lingual swellings = they proliferate + enlarge = overtake the medial swelling (tuberculum impar) = will give rise to the tongue 

   1. The neural crest cells derived menschyme in Arch 1 =  helps proliferate

2. Week 5: rapid development of lateral lingual swellings = grow over the medial swelling + begin to fuse at the midline

3. Week 6: tongue structure is recognisable

   1. Skeletal muscle (derived from the occipital somite) = have voluntary control over it 

   2. Connective tissues + nerves (derived from the neural crest cells)

   3. Epithelium (derived from surface ectoderm) 

   4. ‼Cell death = separates tongue from underlying tissue + leaves behind the frenulum 
      
      

4. Week 8: formation of basic tongue structure

   1. CRITICAL for taste, perception, swallowing, chewing, speech

what pharyngeal arches are responsible for tongue innervation?

Tongue Innervation (derived from the neural crest cells in the pharyngeal arches):

• Pharyngeal Arch 1: 

  • Touch / Pain / Temp: CN V3 = trigeminal nerve (lingual branch)

• Pharyngeal Arch 2: Taste: CN VII = facial nerve

• Pharyngeal Arch 3: 

  • Touch / Pain / Temp / Taste: CN IX = glossopharyngeal nerve

• Pharyngeal Arch 4: vagus nerve (for palatoglossus nerve)

• Motor: CN XII = hypoglossal nerve —> from occipital somites

what are two problems that are related with tongue development:

Anklyglossia (Tongue-Tied)	Cleft Tongue (Bifid Tongue)
~8% newborns affected Cause: the cell death of the tongue with underlying tissue hasn’t fully occurred Associated with speech + feeding disorders  Treatment: frenectomy (removal)	~0.8% of newborns Cause: the lack of fusion of the lateral lingual swellings at the midline Associated: speech + feeding disorders Treatment: surgery

what pharyngeal arches give rise to the larynx?

4 and 6

what is the development steps for the larynx?

1. Week 4: Laryngotracheal groove → gives rise to opening of trachea

   • By Week 4: it gets bigger = call it laryngeal orifice

   • Endoderm cells (outside) will migrate → form the vocal cords

2. Week 6: 

   • Mesoderm cells from Arch 4 + 6 → forms swellings around the laryngeal orifice to form cartilage + muscles

     1. Epiglottic swelling → will form epiglottis

     2. Arytenoid swelling → will form arytenoid cartilage 

     3. arch 4 = epiglottis, thyroid cartilage, cricothyroid muscle

     4. arch 6 = cricoid cartilage, cuneiform cartilage, corniculate cartilage, arytenoid cartilage, laryngeal muscles

   • Endoderm cells → forms the lining of the larynx 

   • Neural Crest Cells → forms the vagus nerve

3. Week 12: the larynx is fully developed = lined with endoderm derived epithelium

what pharyngeal arches give rise to the lungs?

4 and 6

what are the developmental steps for the lungs?

1. Week 5: Trachea & Lung are formed from the lung bud of the primitive foregut

   1. The bifurcation of the lungs are shaped by morphogens 

2. Week 5-16:

   1. ~16 divisions to reach terminal bronchiole

   2. Respiration NOT possible

   3. Fetuses born cannot survive

3. Week 16-23:

   1. Terminal bronchioles divide → primitive alveolar sacs developed

   2. Some respiration possible IF premature birth, BUT require a lot of support

4. Week 24 - birth:

   1. More alveoli develops

   2. Epithelium lining is thin enough = allows respiration 

   3. Surfactant production begins → creates enough surface tension to prevent alveoli collapse, and allows them to open up

      1. If baby is born before 24 weeks, they need an injection as they CAN’T produce surfactants

      2. Have a higher chance of survival ~ 50%

5. Birth - 8 year old

   1. Lung development continue until 8 years of age, esp because in utero there is no access to oxygen // getting oxygen + removes CO2 through placenta 

   2. ⅓ of fully formed alveoli present at birth 

      1. Babies first breath opens up the system → then ready to breathe

   3. Respiratory bronchioles, terminals, alveolar ducts continue to increase in number

what is oesophageal atresia and trachoesophageal fistula?

• Causes:

  • improper differentiation + elongation of the esophagus = termination of the pipe 

  • Fistula = opening in the wrong area as they are opening on either side

• Problem: can’t send food down to stomach / have food will result in food going in the wrong pipe

• Treatment: surgery 

what are the embryonic origins for these parts of the ear?

what are the steps for the development of the ear?

1. Week 4: (D22-24)

   1. Thickening of surface ectoderm= the cells begin to elongate → simple columnar epithelium cells

      1. Morphogens are working on this area = begins to invaginate to form a otic placode

*

2. D28: Otic Pit formed (the invagination goes so deep)

2. Week 5:

   1. D30: The otic pit pinches off to form an otic vesicle (otocyst) → closer to the neural tube

3. Week 6:

   1. Otocyst → develops into the membranous labyrinth 

      1. The cochlear portion (cochlear duct) → gives rise to the saccule + cochlear duct

      2. Vestibular portion (saccule) → gives rise to semicircular canals + utricles

4. Week 7: the cochlear duct makes a turn

   1. Week 8: makes a 1.5 turn

5. Week 10: 

   1. Production of semicircular canals

   2. Production of utricle + saccule = helps with vertical + horizontal motion

   3. 2.5 turns of cochlear duct 

how does the organ of corti develop?

• Differentiation: 8-10 wks

• Synaptogenesis: where the synapses of the neurons that connect to the vestibulocochlear nerve (16-20 wks)

• Hearing (26-29 wks)

what are the causes of malformation of the middle / external ear + symtpoms?

Malformation of Middle Ear	Malformation of External Ear
Congenital atresia (blockage) of external auditory canal Failure of canalisation of meatus to FORM auditory canal ~1/8000 births	Cause: maternal exposure to accutane Symptoms: during 1st trimester, disrupts normal development Craniofacial defects (small / absent ears, auditory + visual issues, cleft palate)

what is teratology

factors that cause birth defects

what are 2 importatant factors required for a teratogen to cross the placenta?

Molecular Weight (MW)

• MW > 1000 = does not easily cross the placenta

• MW < 60 = can cross the placenta by simple diffusion or transporter (SHOULD BE AVOIDED)

• Most drugs: MW 250–400 (pregnant women have to be careful of what they take)

Hydrophobicity: ability to cross through a plasma membrane

what are key features that determine an embryo’s susceptibility to birth defects?

• Conceptus (embryo / fetus when conceived) genotype

  • Embryos can have the same exposure with varied susceptibility due to their genetic components

  • E.g Sickle Cell Anaemia → HbAs = protection from malaria // HbAA = susceptible to malaria

• Environmental factors

• Dose

• Timing and length of exposure

what are the weeks for “safe” / “critical period of development” / “less critical”/

safe = 0-2 weeks

critical = 2-8 weeks

less critical = >8 weeks

what happens in the critical period of the development?

ORGAN DEVELOPMENT formation of:

• CNS

• lower limbs

• heart

• upper limbs

• eyes

• ears

• lips + midface

• palate

• teeth

what happens in the less critical stage of development?

maturation of the organ structures

• formation of external genitalia

what are 5 main aetiology (causes) of birth defects with examples of each?

Point mutations (7.5%)	Chromosomal Anomalies (6%)	Environmental (5%)	Multifactorial (20%)	Unknown (61.5%)
Cystic fibrosis Sickle cell anaemia	Trisomy 21	Alcoholism Rubella CMV Accutane Thalidomide	Familial cleft lip and palate Spina bifida

what is thaliomide? its cause? symptoms? the critical stage of development affected?

Causes

Thaliomide initially used as a sedative and sleeping tablet Subsequently prescribed for nausea and vomiting in pregnancy Critical Stage of Development Affected: Limb Development (esp during 20-30 days post fertilisation) The med disrupted the protein degradation It is anti-angiogenesis = limbs rely on rapid blood vessel growth → thalidomide targeted + destroyed newly formed blood vessels Signal Disruption: disrupts bone + tissue patterning

Symptoms

Stunted limb development extreme tirdness

what is the cause of anticonvulsants like valproate and carbamazepine? and its symptoms?

Causes	Used to: treat epilepsy Critical Development Stage Affected: facial development (occurs earlier in the development) The drug disrupts the fusion of the facial processes
Symptoms	Facial Abnormalities (typical facies) 2% risk of neural tube defects

what is the effects of a mother having rubella on her fetus? what are the symtpoms? and risks?

Symptoms	In the Mother: airborne // mild rash + fever In the Conceptus:  Congenital cataract Sensorineural deafness: collapsed organ of corti + damaged stria vascularis (affects the production of Action Potentials to signal sound)
Risk	1st Trimester: 25% risk 1st month: 50-70% risk 2nd Month: 22-40% risk

what is the effects of a mother having alcohol while pregnant? and its cause?

Causes	BOTH male and females can be affected by alcohol (the males sperm can also be affected) Impacted Developmental Stage: Facial Development (problems with its fusion) 60% chance of FAS → if alcohol is consumed during pregnancy
Foetal Alcohol Syndrome	Microcephaly = small head / brain Facial deformities: wide-spaced eyes, thin upper lip, indistinct philtrum Mental retardation Sensorineural deafness Behavioural problems Growth impairments

what is the effect of folic acid deficiency while pregnant?

Neural tube defects:

• 0.2-0.4% pregnancies

• INCREASES risk of spina bifida

Folic acid before Pregnancy

• reduces risk by 50-70%

• Average person needs 0.4 mg/day

• 5 mg/day for people with epilepsy, diabetes, or family history of NTD

what are the 3 steps followed in drug testing?

1. preclinical testing (lab testing on cell lines / small animals / large animals)

2. clinical trials (safety + efficacy)

3. epidemiology (population based)

what is treacher collins syndrome? its cause? facial abnormalities?

Treacher Collins Syndrome
Cause	Excessive cell death (apoptosis) in cranial neural crest cells = form the facial bones + tissues → hypoplasia of Arch 1→   failure of the cells to migrate to pharyngeal arches 1 and 2
Facial Abnormalities	Hypertelorism: larger gap between eye position Microtia: very small ears (unusually formed / missing) Improper canalisation of the ear Mandibular hypoplasia: small jaw that is bilateral Downward slanting outer corners of the eyes

what is the relation of embryological development and treacher collins syndrome? what is its impact on speech etc.?

Embryological Basis	hypoplasia (underdevelopment) of Arch 1
Impact of Speech / Swallowing / Hearing	Shortening of the mandible → airway obstruction  Infants can have feeding difficulties due to macrostomia affecting lip seal and palate dysfunction.  Swallowing coordination problems can occur.

what is goldenhar syndrome? its cause? facial abnormalities? embryological basis?

Cause	Abnormal development of neural crest cells + mesoderm derivatives in pharyngeal arches 1 and 2 = disruption of normal face development
Facial Abnormalities	Face / Jaw: Hemifacial microsomia Facial asymmetry Unilateral facial nerve palsy Lack of bone development on the affected side Macrostomia (big mouth) Ears: Microtia External / middle ear abnormalities Periauricular ear tags (lack of fusion of early development structures) Eyes: Eyelid abnormalities (coloboma)
Embryological Basis

what is noonan syndrome? its cause? facial abnormalitiies? relation to embryology?

Cause	Affects neural crest cell migration + pharyngeal arch development → malformations in craniofacial development
Facial Abnormalities	Hypertelorism: large space b/w eyes Pale blue / green eyes + pale skin → neural crest cells are also involved in pigmentation Low-set ears Depressed nasal bridge Deep philtrum Facial droop Large forehead
Embryological Basis	Caused by mutations in cell signalling pathways

what is foetal alcohol syndrome? its cause? facial abnormalities? embryological basis?

Cause	Excessive consumption of alcohol during pregnancy Leading cause of preventable birth defects Alcohol passes through the  placental – into foetal circulatory system = effects of alcohol on foetus (during gestation period) Migration + survival of neural crest cells = impacts pharyngeal arches → subsequent facial structure developments Toxic by-products of alcohol: negative effect on central nervous, visual, auditory, cardiovascular, renal, skeletal systems
Facial Abnormalities	Flat philtrum Thin vermillon (thin lips) Hypertolerism (wide spread eyes) CNS: focus / memory / learning / behaviour / coordination / hyperactivity ALL affected
Embryological Basis

what is pierre robin sequence? its cause? facial abnormaliities? embryological basis? effect on speech etc.?

Cause	Sequence of disruptions → lead to malformation in and around the mouth Beings in 7th - 11th week of gestation = underdeveloped jaw → small oral cavity → tongue falls backwards = palate malformations
Facial Abnormalities	Micrognathia: stunted chin Glossoptosis: posterior displacement of tongue (affects swallowing + speech) Secondary cleft palate (hard + soft)
Embryological Basis
Effect of speech / swallowing / hearing	Primary management involves surgery to decrease airway obstruction. Children with Robin sequence need continuing therapy for speech and feeding especially when tongue position is the primary cause of the obstruction.