Deuterostome Developmental Biology PDF

Deuterostome Developmental Biology Mostly with respect to vertebrates, but we’ll do some of the other stuff too. Li, et al. 2019. Developmental Dynamics.  Let’s start with a simple question. Jacobson and Tam. 1982. The Anatomical Record. Where is the top of th...

Deuterostome Developmental Biology Mostly with respect to vertebrates, but we’ll do some of the other stuff too. Li, et al. 2019. Developmental Dynamics.  Let’s start with a simple question. Jacobson and Tam. 1982. The Anatomical Record. Where is the top of this sphere? Where is the left? Where is the front? If I were to ask this to a primary school audience: This is the top. This is the left. This is the front. In the absence of any additional information, all reference frames are equally valid. Coordinate systems, like the one superimposed here, are artificial constructs! So, this could easily be the situation as well. Left? As could any of an infinite number of other orientations. Front? Top? Now, let’s bring this back to biological reality. Where is the ‘top’ of this fertilized ovum? And yet, by the time we are born there are very definite: top/bottom left/right front/back axes in the human body. So how does the vertebrate body go from this… …to this?  Assembling the vertebrate Bauplan Etienne Geoffroy Saint-Hilaire 1818. Philosophie anatomique Some basics. Phylogeny of the Metazoa Effectively = “animals” Cnidaria: Corals, jellyfish and related taxa Ctenophores: The “Comb Jellies.” Not true jellyfish. A basal, paraphyletic group of vaguely radially symmetrical animals Porifera: Sponges  Phylogeny of the Metazoa Effectively = “animals” Bilateria The bilaterally symmetrical animals. Or some modification thereof…  Phylogeny of the Metazoa Effectively = “animals” Bilateria is further subdivided into: Protostomes (blue) and Deuterostomes (red).  Phylogeny of the Metazoa Effectively = “animals” Deuterostomes  Deuterostomes Echinoderms: Literally: “spiny skin” Refers to the endoskeleton of calcium carbonate ossicles in the dermis. Sea Stars, Sea Lillies, Urchins, and several related groups. A diverse clade, both taxonomically and morphologically. Mespilia globulus  Deuterostomes Hemichordates: Literally: “half-chordates” Acorn worms (top) and Pterobranchs (right). Not very diverse taxonomically, but an interesting group. Tunicates: Deuterostomes Sea squirts, salps Urochordates, members of the Chordata, but not vertebrates.  Deuterostomes Vertebrates: Petromyzontiformes (lampreys) True vertebrates, even though there is no bone in them. Vertebrates: Deuterostomes These are more along the lines of what you think when someone says “vertebrate”: something with bones. Frog fish The Fossa African Clawed Toad White-necked Jacobin Deuterostome Body Plan Large disparity in living body plans. What could possibly unite sea squirts, sea stars, and giraffes? Look to development. Hervas et al. 2015. Amphibian and Reptile Conservation. The basic shared characteristics of deuterostomes taxa emerge in early embryogenesis. The Canonical “Five Characters Uniting Chordata.” A Generalized Chordate (Just a cartoon model – No chordate really looks like this.) Notochord: [mesoderm origin] axial rod; vacuolated cells – fluid filled; dorsal to body cavity; ventral to CNS; thick fibrous sheath; function - flexible and resists compression THIS IS NOT THE SPINAL CORD! The spinal cord is part of the central nervous system. This is strictly a structural component. Dorsal nerve cord: [ectoderm origin] – formed by invagination of embryonic neural plate; dorsal to the gut and the notochord; hollow throughout THIS IS THE SPINAL CORD! This is the main trunk of the central nervous system. Pharyngeal slits/clefts/pouches: [endoderm origin] – pharynx = Anterior end of gut; slits from out-pushings/pouches of endoderm; mucous production; supported by basket or alternative skeletal apparatus; functions - respiratory & feeding (generally) Postanal tail: [ectoderm & mesoderm origins] – A body extension beyond level of anus & posterior limit of gut; comprised of muscle/notochord/skeletal; function - motor. Endostyle: [endoderm] – Gland at the ventral part of the pharynx. Aids in food capture in filter feeding (mucus). Can fix iodine. Homologous to your thyroid gland. The fifth character. The endostyle would be Most researchers now include a gland at the base somewhere about here. of the pharynx as well – the endostyle. The Canonical Five Characters All chordates share this set of derived characters at some point in their development. And yet, most taxa do not have all five in their adult form. Note to the right, for example, no tail. And no gills. For many species, some of these morphologies are only visible during embryonic development. Bartolomeo Eustachi Tabulae Anatomicae. Completed in the 1550’s; posthumously published in 1714. The Canonical Five Characters Some of these morphologies are only 2 visible during embryonic development. Right: Human embryo at approximately 3 four weeks showing all five. 1 1. Notochord 2. Dorsal nerve cord 3. Pharyngeal pouches 4. Postanal tail 5. Endostyle / thyroid 4 Ontogeny Ontogeny is the developmental history of an individual. Development from fertilization to adult form is unifying concept in comparative biology. Evolution results from changes to development (ultimately at the level of genes). Evolution is therefore the history of divergent ontogenetic trajectories among species. Most of development is conserved (evolutionary signal). The same genes and processes are shuffled to produce new morphologic diversity and new body plans.  Zygote Morula Pharyngula Blastula A simple schematic ‘Neurula’ Gastrula Cleavage Protostomes Synchronous cell division from the single-celled zygote up to the 16-cell stage (at least in humans) with little to no change in overall size. Radial Cleavage Deuterostomes (most of them…) exhibit radial cleavage, where the daughter cells are aligned with the parent cells. After this stage cell division is stochastic, and size increases. This is the morula stage. Deuterostomes Blastulation Yes, that really is a word. Blastoderm Blastocoel The morula hollows out through further cell division, leaving a fluid-filled space. This is the blastocoel. The cells around the outside are the blastoderm. The embryo is now referred to as a ‘blastula’. Morula Blastula Several important events occur in this stage, including germ layer specification (at least at a very high level) and basic axis polarity formation. Blastulation Frog “embryonic” In most vertebrates (like the frog to the left) the blastoderm differentiates into an ‘animal pole’ and a ‘vegetal pole’. These terms are somewhat outdated, and many people now use ‘embryonic’ and ‘abembryonic’. The vegetal pole will go on to form the yolk mass. The animal pole will form the embryo proper. “abembryonic” Blastulation Placental mammals (like humans) are different: we do not have yolk masses. Human Rather the outer blastoderm differentiates into a trophoblast and an ‘inner cell mass’ or embryoblast. In mammals this is often then called a ‘blastocyst’, for no good reason other than to make you learn yet another word. The trophoblast will go on to form much of the tissue in the placenta. Alternative spelling, also correct. Bat Blastulation Placenta Accreta A disturbingly common condition (~1 in 300 pregnancies). This condition arises when the trophoblast implants too deeply into the uterine wall. (The ‘spectrum’ describes the severity of penetration of the trophoblast.) This is often associated with heavy haemorrhaging during delivery and need for caesarean intervention. In extreme cases (with penetration into the muscle wall of the uterus), a hysterectomy can be required to control potentially fatal bleeding. Gastrulation The textbook echinoderm model Deuterostomy (somewhat tautological) Protostomes - Mouth forms from blastopore (“mouth first”) Deuterostomes - Anus forms from blastopore (“mouth second”) Gastrulation – In a frog: Xenopus Wolpert et al. 2019. Principles of Development. Also, check out link to video of echinoderm gastrulation on Brightspace. Examples of animal embryology from blastula through gastrula Note that the blastula to gastrula transition is fairly uniform across a vast swath of animal diversity. Frog Sea Urchin Snail Fruitfly Examples of animal embryology from blastula through gastrula But it isn’t totally the same. Here are a chicken (left) and a teleost fish (below). Gastrulation one layer two layers Differentiation of the mesoderm Triploblasty Deuterostomes (like many other bilaterians) possess three tissue (‘germ’) layers: Ectoderm Endoderm Mesoderm Ectoderm and endoderm are the direct products of gastrulation. How they differentiate the mesoderm is different. Gastrulation Gastrulation involves four evolutionarily conserved morphogenetic movements: Emboly, moves mesoderm and endoderm cells internal to the ectoderm. Epiboly spreads and thins germ layers. Convergence narrows germ layers dorsoventrally Extension elongates germ layers anteroposteriorly. The three major germ layers arrive in their correct topological positions during gastrulation. The fundamental directional axes of the bodies are now consolidated. Gastrulation As such, the single layer of epithelial cells (the blastula) is reorganized into the multilayered, multidimensional structure of the embryo. Gastrulation also marks the beginning of organogenesis – formation of the organs of the body. "It is not birth, marriage, or death, but gastrulation, which is truly the most important time in your life." Lewis Wolpert 1929-2021 Germ Layer Derivatives You need to know this. Ectoderm – skin, nervous system, the neural crest Mesoderm – most of the skeleton, connective tissue, circulatory system, heart and kidneys, muscles, the notochord Endoderm – gut, out-pocketings of gut: gills and lungs, glands & related tissues; the liver. Hox genes and antero-posterior patterning. Hox expression in mouse embryo, after neurulation – arrow heads indicate anterior expression boundary within the neural tube. Hox genes and antero-posterior patterning. Hox expression pattern along the antero-posterior axis of mouse mesoderm. Note: This is not a sectional arrangement of gene expressions. This is a set of nested combinations. Hox genes and antero-posterior patterning. Chick embryo vs. mouse embryo What are the differences? chick mouse Hox genes and antero-posterior patterning. Transition from one vertebral region to another corresponds with the pattern of Hox gene expression (Burke et al. 1995) Hox genes and antero-posterior patterning. This regionalization occurs very early in development Transplantation of thoracic mesodermal tissue into the neck of another embryo results in formation of vertebrae in the neck region. But they bear ribs as if they were thoracic vertebrae. Neurulation In a frog: Xenopus A cartoon example. And technically only applicable to tetrapods… Wolpert et al. 2019. Principles of Development. The notochord induces formation of the neurectoderm (“neural plate”) to form a hollow neural tube. Watch this again but focus on the part after gastrulation. This then forms the CNS. Neurulation Ectoderm differentiates into neuronal cells automatically, unless BMP-4 signals them to differentiate into skin cells. The notochord secretes chordin, noggin and follistatin: these proteins inhibit BMP-4 signaling (Chambers, et al. 2009. Nature Biotechnology). Therefore, the ectoderm immediately dorsal to the axial mesoderm (= notochord) develops into neuronal cells. Chick embryo, showing the development of the neural tube. Primary vs. Secondary Neurulation Hagfish Sharks ‘Primitive’ actinopts Tetrapods Lamprey Teleosts The tail of all vertebrates 2° What we just talked about is primary neurulation (top row). Secondary neurulation (second row) involves ventral thickening of the neural plate, producing a solid nerve cord ‘medullary cord’. This then becomes secondarily hollow. 1° Primary vs. Secondary Neurulation Hagfish Sharks ‘Primitive’ actinopts Tetrapods Lamprey Teleosts The tail of all vertebrates 2° What we just talked about is primary neurulation (top row). Secondary neurulation (second row) involves ventral thickening of the neural plate, producing a solid nerve cord ‘medullary cord’. This then becomes secondarily hollow. 1° Primary vs. Secondary Neurulation Hagfish Sharks ‘Primitive’ actinopts Tetrapods 2 3 Lamprey 1 Teleosts The tail of all 4 vertebrates Emmm… 2° What we just talked about is primary neurulation (top row). Secondary neurulation (second row) involves ventral thickening of the neural plate, producing a solid nerve cord ‘medullary cord’. This then becomes secondarily hollow. 1° Secondary Neurulation Retained Medullary Cord Normal human development has a medullary cord develop through secondary L1 neurulation, arrest and resorb. L2 The only components that remain form the conus and filum of the terminating spinal L3 cord. The conus usually lies at the level of ±L1/L2 (red). The filum acts as a tether, L4 connecting the conus to the Os coccyx. L5 Left, MRI (same image different filters) of a 1-year-old child. You can clearly see CNS tissue extending fully to the sacral vertebrae (blue shading). This represents a “redundant nonfunctional spinal cord below the true conus”. Pang, et al. 2011. Neurosurgery. Neurulation The anterior portion of neural tube differentiates (elaborates?) into the brain, with three primary (embryonic) regions: 1. Prosencephalon: forebrain (telencephalon + diencephalon) \\\\ 2. Mesencephalaon: midbrain 3. Rhombencephalon: hindbrain (metencephalon + myelencephalon) \\\\\ \\\\ Central canal of he spinal cord expands and folds Early elaboration of the emerging brain in into the ventricle network of the adult brain a standard vertebrate embryo Neurulation Neural Tube Defects are linked to problems during neurulation, most often with proper closure of the neural tube. Spina bifida is the most common NTD. Spina bifida is the result of failure of the neural tube to properly close, and subsequently the spine closing around it. Cases can range from asymptomatic (S.b. occulta) to severe (S.b. myelomeningocele). Neurulation Neural Tube Defects are linked to problems during neurulation, often proper closure of the neural tube. Hydrancephaly (literally ‘water brain’) is the failure of the CNS to form cerebral hemispheres. The cranium is usually filled with cerebrospinal fluid. (Whence the name.) As the hindbrain is intact, infants can suckle and have other instinctual reactions. Most children will die within the first year of life, although in rare cases reach adulthood. Neurulation Neural Tube Defects are linked to problems during neurulation, often proper closure of the neural tube. Anencephaly (literally ‘no brain’) is the failure of the CNS to close at the anterior-most end, resulting in no formation of the telencephalon (forebrain). There is no bone formation and often no skin over the area where the brain should be. Usually just a membranous covering. The hindbrain remains intact. Those that are not stillborn can suckle and breathe without aid. Most die within a couple days. The Neural Crest Neural crest cells (NCCs)are derived from the neurectoderm Pre-patterned ectoderm for development of the neural tube Migration between ectodermal and mesodermal layers (“mesenchyme”) Migration follows evolutionarily conserved pathways/streams Follows the expression of Hox genes Neural crest migration in a Day-25 human embryo. The Neural Crest Stage 20 Stage 21 Mexican axolotl, Ambystoma mexicanum Ectoderm peeled-off to show neural tube & crest streams NT: Neural Tube MNC: Mandibular Neural Crest Stream HNC: Hyoid Neural Crest Stream BNC: Branchial Neural Crest Stream OV: Optic Vesicle (~ Optic Placode) M: Mesoderm Stage 24 Falck et al. 2002. Zoology. The Neural Crest Kulesa and Fraser 2000. Development. The Neural Crest Streams of migrating neural crest cells from the rhombomeric (transiently segmented) region of the hindbrain are confined to specific pharyngeal pouches. Optic cup Otic placode Etchevers et al. 2019. Development. The Neural Crest A fourth germ layer? Neural crest is deployed segmentally, from the CNS. NC Contributes to: Cartilage and bone of braincase anterior to notochord Cartilage and bone of jaw & gill skeleton (visceral arches) Dermal bone (in general) - thus most of the facial bones, jaws, palate, ear and throat structures Some cardiac tissues (valves of heart; great vessels of the heart) Most of the peripheral nervous system – the nervous system external to the brain & spinal cord. Pigmentation Etchevers et al. 2019. Development. Germ Layer Derivatives I’m serious. You need to memorize this. Ectoderm – skin, nervous system, the neural crest Mesoderm – most of the skeleton, connective tissue, circulatory system, heart and kidneys, muscles, the notochord Endoderm – gut, out-pocketings of gut: gills and lungs, glands & related tissues; the liver. Cross section of a vertebrate embryo after neurulation The ‘neurula’ stage. Notochord We now have: A tube with a defined anterior and posterior end. Outer, inner, and middle tissue layers. A structural component down the dorsal midline (so a back and stomach side of the animal). Neural crest moving A hollow tube of neuronal tissue dorsal around in here. to this. An internal cavity within the middle layer. Migrating neural crest cells going all over the place. 3D reconstruction (CT scan) of a human embryo after neurulation Somewhat later on… Human embryo at Carnegie Stage 11 (approximately 29 days post fertilization) Human Developmental Biology Resource Atlas www.hdbratlas.org/ Recall this slide. Pharyngula Two mammalian embryos at or near the “limb-bud” stage. Which is the mouse, and which is the human? Pharyngula mouse human Two mammalian embryos at or near the “limb-bud” stage. This is the point; at this stage it is very hard to differentiate between mammalian species. Pharyngula At the pharyngula stage, most vertebrates look pretty much alike. It is after this stage of development that ontogenies diverge, and we get morphological differentiation. Pharyngula Note the Carnegie Stage 14 human embryo to the right. I have highlighted the germ layer sources for the emerging upper and lower jaws in blue. For now, note yellow and red. These are transient pharyngeal pouches. Like we already saw in the mouse. Kuratani 2005. Zoology Kimmel and Eberhart 2008. Integ. Comp. Biol. Branchial Cleft Cysts Swelling in the upper part of neck, usually anterior to the m. sternocleidomastoideus. It can, but does not usually, open to the skin surface. The cause is a developmental abnormality of failure to obliterate the embryological branchial (=pharyngeal) clefts. sternocleidomastoid muscle head Segmentation of the vertebral column. In a way, the defining feature of the vertebrates. William Cheselden 1733. Osteographia. Segmentation of the vertebral column. ? They differentiate from anterior to posterior. Moreover, this appears to involve addition of segments at the posterior end. The total number of vertebrae in the spine, and the counts within types of vertebrae vary across species. We saw this already. For adult humans it is 7 cervical verts, 12 thoracic, and 5 lumbar, plus some others fused together to form the sacrum and the Os coccyx. William Cheselden 1733. Osteographia. The counts within types of vertebrae vary across individuals within a species. For adult humans it is 7 cervical verts, 12 thoracic, and 5 lumbar, plus some others fused together to form the sacrum and the Os coccyx. But not ALL humans! Garg et al. found that up to 20% of patients with Adolescent Idiopathic Scoliosis had a non-standard number of thoracic and/or lumbar vertebrae. Look at the person to the right with 11 thoracic verts. Failure to account for non-standard phenotypes leads to increased risk of wrong-level surgery – one of the surgical ‘Never Events’. Garg, et al. 2021. Int J Spine Surg. Lindley et al. 2011. Patient Safety Surg. How? If we delete the HoxD enhancer (RVIII) we delay Hoxd11 expression in the presomitic mesoderm. Mouse showing a vertebra in the physical position of the 1st sacral vertebra, but with the morphology of the preceding lumbar region (right). Onset of sacral morphologies is ‘phase-shifted’ toward the tail by one vertebral position. “Wild type” RVIII deletion Again… Zákány et al. 1997. EMBO Journal The Vertebral Column Re-segmentation of the vertebral column (at least in amniotes). The Vertebral Column Re-segmentation of the vertebral column (at least in amniotes). Ventral roots of the spinal nerves induce separation along the ‘middle’ of the initial somites. Anterior and posterior ‘halves’ then reform into the segments that constitute the adult vertebral bodies. You are more segmented than you think. Dermatome map showing enervation of sensory and motor neurons from the CNS. Spinal sensory/motor nerve roots exiting between the vertebrae. This is in the cervical region, but the same system repeats the pattern throughout the body. You are more segmented than you think. Shingles (Varicella zoster virus) Often called chickenpox for childhood infections. The virus can remain dormant in the dorsal root ganglia or cranial nerves for years or decades. After time, it may reactivate, following nerve bodies, resulting in painful sores on the body or face. The mechanism for this is not known. Note that, when presenting on the trunk, the virus often travels along nerve pathways following the dermatome map. You are more segmented than you think. Peyton Manning Then with the Indianapolis Colts of the NFL, spent the 2011 season injured due to a herniated disc between cervical vertebrae 6 and 7. Suffered from C7 radiculopathy – numbness and weakness in the arm. Particularly in the triceps and in the middle fingers of the hand. C6/C7 single-level anterior cervical fusion Palmar Dorsal You are more segmented than you think. We’ve talked a lot about disorders that arise due to, and symptoms that follow from, developmental constraints. How about a disorder that you CANNOT have due to developmental constraints? Again, ventral/palmar, left; dorsal, right You are more segmented than you think. How about a disorder that you CANNOT have due to developmental constraints? Dermatome map of the human right arm showing spinal nerve inputs from the CNS. Three nerves enervate the human hand, originating between the 5th/6th cervical vertebrae (C6), the 6th/7th cervical vertebrae (C7), and the 7th cervical/1st thoracic vertebrae (C8). Glove Anesthesia and Functional Neurologic Symptom Disorder (Older terminologies called it ‘Conversion Disorder’) Again, ventral/palmar, left; dorsal, right You are more segmented than you think. Functional Neurologic Symptom Disorder (Older terminologies called it ‘Conversion Disorder’) The Cranium Embryonic cartilages Braincase - Basic vertebrate embryonic cartilages Support for the three paired sensory capsules Neurocranium Canis lupus familiaris The Cranium Embryonic cartilages Mouse Ant. Neurocranium Pitirri et al. 2020. Vertebrate Zoology. The Cranium Embryonic cartilages otic optic olfactory Lamprey The homology here is, evolutionarily, quite deep. Neurocranium The Arches “Jaws” (Mandibular arch); Hyoid arch; Gill arches Viscerocranium This is how everything fits together Neurocranium branchial / gill arches mandibular arch Viscerocranium hyoid arch  Here are the neurocranium and viscerocranium in a real organism: Porbeagle Shark, Lamna nasus. Making the Arches Recall this slide: Despite their being endochondral bones, the jaw and gill arches are partly derivatives of the neural crest. Compound Structures Making the Arches ‘Rhombomeric’ map of neural crest derived skeletal elements in chick skull (color code marks neural crest cells from specific segments of the hindbrain) Recall also. Endoskeleton (“Endochondral”) Bone preformed in cartilage Possible to retain a cartilage core in some taxa Intra-membranous skeleton (“Dermal skeleton”) Not preformed in cartilage Compact, layered bone, may include dentine and enamel components µCT scan of Gymnotus carapo (banded knifefish). But it is different in mammals (like humans) But note! The jaw joint is between two dermal bones. Human skull highlighting the dermal (shaded right) and No endochondral bones here! endochondral (shaded left) contributions.  I show this image of a human fetus with Meckel’s Cartilage in ZOOL 20030 Principles of Zoology. All of these cartilage elements are present in mammals embryologically. But they are not present in the adult. At least not as jaw elements. 3D digital model of the bones of the middle and inner ear of a gerbil based on CT data. Ceratohyal becomes (part of) the hyoid bone supporting the larynx. Red is the tympanum (‘eardrum’). Note conserved connection of the stapes (purple), which is the embryonic hyomandibula. Note conserved ‘jaw joint’ between the articular (malleus, blue) and quadrate (incus (green). Buytaert, et al. 2011. Journal of the Association for Research in Otolaryngology. Indeed, here are the embryonic cartilage gill arch contributions to adult structures of the pharynx. Endostyle! Ceratohyal becomes (part of) the hyoid bone supporting the larynx. The dermal bones of the face and head Here is more of the same in cartoon format for a generalized vertebrate embryo. Conserved streams of NCCs from the hindbrain move to form the various arches of the viscerocranium. Again. ANT. Mandibular arch Hyoid arch Gill arches ANT. Kuratani 2005. Zoology Kimmel and Eberhart 2008. Integ. Comp. Biol. The dermal bones of the face and head Recall this 32-day human embryo, now looking at the blue in detail. Mandibular arch Hyoid arch Gill arches Mammals have a contribution of the frontonasal prominence (=‘frontonasal process’) to the middle part of the upper jaw. Kuratani 2005. Zoology Kimmel and Eberhart 2008. Integ. Comp. Biol. The dermal bones of the face and head Recall this 32-day human embryo, now looking at the blue in detail. Mandibular arch Hyoid arch Gill arches Mammals have a Cebus olivaceus contribution of the frontonasal prominence (=‘frontonasal process’) to the middle part of the upper jaw. 1 2 1. Maxillary Bone; Source NCCs from maxillary stream. 2. Premaxillary Bone; Source NCCs from FNP stream. Kuratani 2005. Zoology Kimmel and Eberhart 2008. Integ. Comp. Biol. The Neural Crest Pathology associated with neural crest cell population defects. Recall once again: Pathologies are often linked to reduction in the number of cells in NCC populations, to interruptions in their migration, or to changes in the multipotency of these cells.  Cleft Palate Incomplete Complete Unilateral Bilateral Paramedian cleft palate: Unilateral or Bilateral Failure of neural crest cells streams to fully meet at the junction(s) of the frontonasal prominence and the maxillary process(es). Embryology of the human face (from Gray’s Anatomy) Allam, et al. 2011. Plastic and Reconstructive Surgery.  Cleft Palate Midline cleft palate: Failure of the L/R streams of neural crest cells in the frontonasal prominence to meet along the ventral midline. Embryology of the human face (from Gray’s Anatomy) Allam, et al. 2011. Plastic and Reconstructive Surgery. Down Syndrome Aka: Down’s Syndrome, Trisomy 21 Partial or full duplication of one of the 21st pair of chromosomes. There is a wide range of clinical outcomes for this. Characterized by a distinctive set of facial features. Widely set eyes Elongate orbits Reduced or absent nasal bones Weak chin Flattened head Narrow palate Down Syndrome Aka: Down’s Syndrome, Trisomy 21 Partial or full duplication of one of the 21st pair of chromosomes. There is a wide range of clinical outcomes for this. In addition, Congenital problems with the heart are common. Hearing loss / difficulties are common. Palatal clefting is more common than the general population, although still rare overall. Down Syndrome Aka: Down’s Syndrome, Trisomy 21 DiGeorge Syndrome Aka: 22q11.2 Deletion Syndrome Deletion of approximately 30 to 40 genes from the long arm of Chromosome 22, resulting in about 1.5 million basepairs of DNA missing from the chromosome. McDonald-McGinn, et al. 2015. Nat Rev Dis Primers. Characterized by a similar set of facial features to Down Syndrome, although these are generally considered milder than Trisomy 21. Palatal clefting is much more common in people with DiGeorge Syndrome. As is thyroid dysplasia – from incomplete separating of the embryonic pharyngeal pouches. DiGeorge Syndrome Aka: 22q11.2 Deletion Syndrome Congenital heart problems, including persistent truncus arteriosus. This is a failure of the embryonic truncus arteriosus to divide into separate aorta and pulmonary arteries (aorticopulmonary septum). The cardiac NCC population is responsible for this division. Often associated with the ‘Tetralogy of Fallot’ 1. Pulmonary stenosis, narrowing of the exit from the right ventricle 2. Ventricular septal defect, a hole allowing blood to flow between the ventricles Normal Circulation 3. Right ventricular hypertrophy, thickening of the right ventricular muscle PTA Through the Heart 4. Overriding aorta, expanded aorta allowing blood from both ventricles to enter Patau Syndrome Aka: Trisomy 13 Partial or full duplication of one of the 13th pair of chromosomes. This is considered a very severe trisomy disorder. Survival and intellectual impacts are related to the degree of duplicated genetic material (complete / partial trisomy). Approximately ~90% of children die in the first year of life. Clefting of the palate, deformation of the facial and braincase bones and holoprosencephaly (failure of the forebrain to divided into left and right hemispheres) are all common associated phenotypes. Heart defects are also common. Waardenburg Syndrome Caused by mutations in several genes that affect the neural crest cells. Division and proper migration of the NCCs is interrupted. Can be characterised by increased inter-orbital spacing, misalignment of the orbits and often a prominent white forelock. Hearing loss is also common. Other, more severe, symptoms also rarely exist. Hirschsprung’s Disease Birth defect in which nerves are missing from parts of the intestine. Failure of neural crest cells to completely migrate to the entire intestine. The result is a section of the intestine that cannot relax, and therefore cannot pass stool. It can occur on its own, but it is often associated with Down Syndrome or Waardenburg Syndrome. Distended colon observed in a pediatric case of Hirschsprung’s Disease.  None of these is primarily a condition of the NCCs! Each of these conditions is the result of specific genetic mutations/deletions/duplications. In each, neural crest cell populations are impacted during neurulation causing characteristic downstream symptoms. The exact mechanism(…s???) of why and how NCC populations are affected by trisomy of the 21st chromosome, for example, are completely unknown.