Neonatology and the Developmental- Neonatology and the Developmental- Evolutionary ParallelEvolutionary Parallel

• Endodermal and Ectodermal Tissues follow a common developmental sequence throughout all vertebrates

• Disruption of this developemental sequence results in predictable consequences

• In the surviving neonate, the consequences of developmental disruption equal congenital anomalies (e.g. holoprosencephaly, pulmonary hypoplasia) or morbidities of prematurity (e.g. RDS, apnea of prematurity).

• We can flip this logic around by asking ourselves, “how can the developmental – evolutionary parallel be used to better understand these diseases?”

What is the Developmental- What is the Developmental- Evolutionary Parallel?Evolutionary Parallel?

500,000,000 years ago Today

Development: 10 weeks 20 weeks 30 weeks 40 weeks

Perturbations are associated with

congenital anomalies

Perturbations are associated with diseases of prematurity and birth

The limits of The limits of viabilityviability

Perturbations result in spontaneous

abortions

The mesoderm is unfaithful in terms of the developmental – evolutionary parallel. By 21 days, the mesoderm of the human fetus has created the basic form of a salamander, but it takes another 21 weeks before the endoderm and ectoderm mature sufficiently for viability (at the saccular stage of lung development). But endoderm and ectoderm are faithful because of growth factor ontogeny (more later).

500,000,000 years ago Today

Polymicrogyria

-/- PAX 6 (no pineal gland and…)

Notochordata (lampreys, lancets, hagfish)

Ram Jet Ventilation

Does he have 3 eyes too?

GI tract = stoma + gut tube

The lamprey gives us our The lamprey gives us our hypothalamus, pituitary / pineal hypothalamus, pituitary / pineal

tracts and basal brain stem nuclei.tracts and basal brain stem nuclei.

2 = the notochord

Pineal gland (the 3rd eye)Larvea

500,000,000 years ago Today

Development: 10 weeks 20 weeks 30 weeks 40 weeks

Elasmobranchs have 13 Elasmobranchs have 13 cranial nerves #13 = the cranial nerves #13 = the nervous terminalis (an nervous terminalis (an

accessory olfactory nerve)accessory olfactory nerve)

“The brain follows the nose” holoprosencephaly

Elasmobranchs have Elasmobranchs have keen smell and well keen smell and well developed olfactory developed olfactory

cortexcortex

Elasmobranchs part 1

proximal to distal proximal to distal gut developmentgut development

BMPBMP

IGF-I + IGF-IIIGF-I + IGF-II

FGF10FGF10

500,000,000 years ago Today

Development: 10 weeks 20 weeks 30 weeks 40 weeks

Elasmobranchs part 2

Some Elasmobranchs develop the first gill Some Elasmobranchs develop the first gill chambers (operculums) and along with it they chambers (operculums) and along with it they

develop develop primary respiratory driveprimary respiratory drive (a brain (a brain stem function). In parallel with evolution, fetal stem function). In parallel with evolution, fetal

breathing starts in the first trimester.breathing starts in the first trimester.

If a fetus can’t breath in fluid (due If a fetus can’t breath in fluid (due to a swallowing defect, neuro or to a swallowing defect, neuro or muscular defects, or insufficient muscular defects, or insufficient

amniotic fluid) the result is amniotic fluid) the result is pulmonary hypoplasiapulmonary hypoplasia

Elasmobranchs gave us our brainstem, cranial Elasmobranchs gave us our brainstem, cranial nerves and first highly developed lobe of cortexnerves and first highly developed lobe of cortex

500,000,000 years ago Today

Development: 10 weeks 20 weeks 30 weeks 40 weeks

Boney Fish

Fish bring two crucial things to the developmental-Fish bring two crucial things to the developmental-evolutionary parallel: evolutionary parallel:

11stst – they evolve the first high resolution, complex – they evolve the first high resolution, complex eye into being (which comes with the eye into being (which comes with the optic cortexoptic cortex).).

22ndnd – elasmobranchs convert ammonia to urea and – elasmobranchs convert ammonia to urea and permeate their tissues with it for buoyancy. Fish permeate their tissues with it for buoyancy. Fish evolve the swim bladder for buoyancy as well as evolve the swim bladder for buoyancy as well as metanephric kidneysmetanephric kidneys. They excrete all their . They excrete all their ammonia. This become the basis for the terrestrial ammonia. This become the basis for the terrestrial kidney.kidney.

Pop Quiz: what is Pop Quiz: what is this syndrome?this syndrome?

BMPs & BMPs & FGFsFGFs

IGFs & IGFs & TGFTGF

metanephric kidneymetanephric kidney

500,000,000 years ago Today

Development: 10 weeks 20 weeks 30 weeks 40 weeks

The The limit of gestational viabilitylimit of gestational viability is the late cannicular is the late cannicular phase of lung development. Artificial surfactant has little phase of lung development. Artificial surfactant has little

effect on the surface tension of lungs that have no air effect on the surface tension of lungs that have no air sacks but can almost completely normalize saccular lung.sacks but can almost completely normalize saccular lung.

Mature type II Mature type II pneumocytes are required pneumocytes are required to recycle surfactant and to recycle surfactant and may explain why older may explain why older

infants (>30 weeks) require infants (>30 weeks) require fewer repeat doses.fewer repeat doses.Surfactant deficiency = respiratory distress syndromeSurfactant deficiency = respiratory distress syndrome

Amphibians stop here

Amphibians part 1

BMP, EGF, FGF, TGFBMP, EGF, FGF, TGF, VEGF, SPARC, VEGF, SPARC

THTH

500,000,000 years ago Today

Development: 10 weeks 20 weeks 30 weeks 40 weeks

Amphibians part 2

Cloaca Cloaca evolves as amphibians evolves as amphibians must hide their feces from must hide their feces from

predators & carry their eggs to predators & carry their eggs to water (precurser to colon and water (precurser to colon and 11stst durable gut modification durable gut modification

since elasmobranchs).since elasmobranchs).

BMP + ?BMP + ?

* Optic cortex and retinal * Optic cortex and retinal density reach the optimum now density reach the optimum now that amphibians have to track that amphibians have to track flying prey (flying prey (Bufo MarinusBufo Marinus).).

ELBW infants have extreme insensible water loss. If poorly ELBW infants have extreme insensible water loss. If poorly managed it leads to hypernatremia and is associated with IVHmanaged it leads to hypernatremia and is associated with IVH

KGFKGF

*The *The skin becomes keratinized skin becomes keratinized and semi- permeable to water and semi- permeable to water as as

amphibians forage onto land.amphibians forage onto land.

SIP SIP occurs because the occurs because the distal small intestine distal small intestine

(ileum) is “under grown” (ileum) is “under grown” in comparison to the in comparison to the

proximal bowel, which proximal bowel, which distends it and perforates distends it and perforates

it with bowel gasit with bowel gas

Proximal – Distal effectProximal – Distal effect

““Reptilian lung”Reptilian lung”

500,000,000 years ago Today

Development: 10 weeks 20 weeks 30 weeks 40 weeks

Reptiles

KeritinizationKeritinization is more complete after 28 weeks of is more complete after 28 weeks of gestation and water loss is less profound. gestation and water loss is less profound.

Keritinization can be accelerated by stress.Keritinization can be accelerated by stress.

Reptiles have Reptiles have aveolar lungs and aveolar lungs and aveolar histology aveolar histology emerges after 34 emerges after 34

weeks of weeks of development, development,

coincident with coincident with final maturation final maturation

of type II of type II pneumocytespneumocytes

Apnea of PrematurityApnea of Prematurity resolves around 30- resolves around 30-32 weeks of gestation when the nuclei of 32 weeks of gestation when the nuclei of

the respiratory drive centers mature fully. the respiratory drive centers mature fully. Reptiles are the 1Reptiles are the 1stst vertebrates fully vertebrates fully dependent upon active respirationdependent upon active respiration SNOSNO

500,000,000 years ago Today

Development: 10 weeks 20 weeks 30 weeks 40 weeks

Mammals part 1

Development: 20 weeks 30 weeks 40 weeks

Preterm NEC Term NEC

Transient TachypneaTransient Tachypnea is a disease of is a disease of term infants that results from failure term infants that results from failure of clara cells and type II cells to insert of clara cells and type II cells to insert ENaC in the cell surface (associated ENaC in the cell surface (associated

with c-sections / rapid progression) due with c-sections / rapid progression) due to insufficient cortisol exposure.to insufficient cortisol exposure.

Pre- ileocecal valvePre- ileocecal valve bacterial overgrowth bacterial overgrowth formula feeds formula feeds functional ileus functional ileus

Post ileocecal valvePost ileocecal valve isechemic preconditions isechemic preconditions

formula feeds formula feeds rapid feeding advances rapid feeding advances

s[cortisol] during

pregnancy

More Proximal – Distal effectMore Proximal – Distal effect

Long gestations require large

meconium resevoirs

500,000,000 years ago Today

Development: 10 weeks 20 weeks 30 weeks 40 weeks

Mammals part 2

The phenomenon of postnatal brain The phenomenon of postnatal brain development in higher mammals (primates)development in higher mammals (primates) has created additional opportunity for has created additional opportunity for developmental perturbation. There are two developmental perturbation. There are two primary mechanisms of insult:primary mechanisms of insult:

1) hypoxia-ischemia, which can occur either 1) hypoxia-ischemia, which can occur either secondary to anoxic birth injury or in concert secondary to anoxic birth injury or in concert with prematurity and the combination of low with prematurity and the combination of low O2 tensions + low flow statesO2 tensions + low flow states

2) Inflammatory cytokines 2) Inflammatory cytokines associated with sepsis make associated with sepsis make premature infants even more premature infants even more vulnerable to PVLvulnerable to PVL

PVL is associated with PVL is associated with cerebral palsycerebral palsy

500,000,000 years ago Today

Development: 10 weeks 20 weeks 30 weeks 40 weeks

So What?So What?

The Take Home Message:The Take Home Message:

Fetal Fetal DevelopmentDevelopment

EvolutionEvolution

Neonatal Neonatal DiseaseDisease

PerturbationPerturbation

NeonatologyNeonatology

Neonatal Neonatal Well BeingWell Being

versusversus

prematurity prematurity infection infection teratogens teratogens gene defects gene defects