2017 no case should the answer fill more than

2017 Final examination for Gene 505 Openbook test. This test is designed to assess your level of understanding of theconcepts described in the lectures and in the readings and your ability to seekout and integrate knowledge across the three domains of this course. You mayuse Carlson, Epstein, or any other book or published source to research youranswer.

You do not have to give citations, but you may not copy and paste textfrom any source.  Youranswer should be as concise as possible, in no case should the answer fill morethan one side of a piece of paper with 1″ margins and a reasonable sized font(Geneva, Times, or Helvetica 12 point). Your grade for that question will bereduced ½ grade for each answer that exceeds this limit. Theanswers should be emailed to me by Saturday Dec 16 at midnight EST. Testsreceived between 12:01 am Sunday Oct 28 and midnight Sunday Dec 16 will have afull grade scoring penalty. Tests received after that will not receive a gradeand considered incomplete. If you have a serious medical or family emergencythat precludes competing the examination by the due date, please discuss thiswith me. Do notreuse an example from one question in another question.

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Do not reuse an answerfrom your midterm. Suggestion: to avoid frustration, read all of the questionsbefore you answer the first one so you can decide which examples you wish touse in which answers. Remember to include all three elements in each answer.  Pleasesend the answers as an attachment to an email message with the followingfilename: FT505_17_XXX.

doc (replace “XXX” with your initials). Please alsoreplace the footer text with your name (you only need to do this once, itcarries through to all pages). Bytyping your name here, you agree that you have neither received assistance fromanother individual on this examination nor provided assistance to anotherstudent and that what you have written here is original. NAME: Ariel Martinez1. A relatively uncommon, but not extremely rare phenotype is apartially or completely fused midline eye with a tube-like proboscis above that eye.

Explain why in thisdefect that the nasal structure is above (cranial or anterior) to the ocularstructure whereas in the normal, the nose is mostly below (caudal or inferior)to the eye.Synophthalmia andproboscis are rare craniofacial features characteristic of severe holoprosencephaly(HPE), a midline developmental defect that affects 1 in 250 conceptuses. Ahallmark manifestation of HPE is the failure of the forebrain to completelyseparate during early development, influencing the surrounding craniofacialstructures and resulting in the various facial malformations. Classic HPE canbe divided into various types depending on clinical severity: alobar (mostsevere), semilobar, lobar, and middle interhemispheric variant (less severe).

Typicalbrain findings include interhemispheric fusion (complete or partial),monoventricle, and agenesis of the corpus callosum. Common craniofacialfindings in individuals without severe features (such as synophthalmia and aproboscis) include microcephaly, hypotelorism, depressed nasal bridge, singlemaxillary central incisor, and cleft lip and/or palate.Thechief events in HPE occur during gastrulation (week 3 of life), as a result ofsonic hedgehog (SHH) signaling defects.

One of the key signaling centerscrucial for HPE pathogenesis is at the most anterior portion of the midlinemesoderm, the prechordal plate (PCP). Several signaling molecules, including SHH,originate in the PCP and trigger a secondary patterning center in the ventralforebrain. The eye field originates as a continuous structure anterior to andaround the PCP in late gastrulation and its left-right separation is induced bySHH with the help of two other key factors, SIX3 and RAX. SIX3 and RAX haveanti-BMP and anti-WNT activity and create a zone in the eye field and forebrainwhere these signals are neutralized. Mutations in SIX3 cause HPE withsynophthalmia.SHHand FGF-8 have an essential role in face development.

Structures of the face beginto form around week 4-5 from various processes around the stomodeal opening: asingle frontonasal prominence at the rostral most part for the face, pairednasomedial and nasolateral processes, and paired maxillary and mandibularprocesses. The frontonasal ectodermal zone in the frontonasal prominence is animportant SHH signaling center in face formation. The nose arises from the bilaterallysymmetrical nasomedial and nasolateral domains, that migrate medially and fusein response to FGF signaling as the frontonasal process recedes from thestomodeum.

SHH signaling also allows lateral expansion and later formation ofmedial bone structures. This is how the nose forms, with two nostrils separatedby a septum and underneath the eyes. If midline SHH signaling is disrupted, thefrontonasal process fails to recede from the stomodeum and the nasal domainsare no longer separated by intervening medial structures. As a result, the alaeof the nose are juxtaposed to form a tubular appendix without a nasal septumthat localizes above the eyes. 2.

A number of organ systems undergo early regionalizationpatterning by one set of genes, then later reorganization and differentiationby another set of genes. Give an example of this.Gastrulation starts in the third week oflife to give rise to three germinal layers: the ectoderm, mesoderm andendoderm.

Through a series of embryonic induction processes mediated bydiscreet groups of genes primordial structures of the embryo develop. Gastrulationbegins with the formation of the primitive streak. At the tip of the streak,the primitive node (organizer) forms to serve as an important signaling centerin early embryo patterning.

Cell of the node express three key markers: Chordin,Goosecoid and FOXA-2. These factors will determine the establishment of variousembryonic structures including the prechordal plate and the notochord. Influencedby Goosecoid and FOXA-2, the notochord also produces Noggin and SHH, which arepotent morphogenic factors.

The notochord willbe crucial in determining the axial patterning of the body and defining differenttissues and organ systems. For example, signals originating from the notochordstimulate the transformation of the overlying surface ectoderm into neuraltissue; transform specific groups of mesodermal cells of the somites intovertebral bodies; and inhibit cardiac mesoderm specification thereby limitingthe size of the cardiogenic fields.In earlydevelopment of the heart, starting approximately at day 15 of gestation in humans,cells anterior to the primitive streak are fated to become heart muscle.

Agonistsand antagonists of the BMPs, FGF and WNT families of growth factors areproduced by the ectoderm and the endoderm resulting in a unique signalcross-talk microenvironment that drives cardiac differentiation. Bilateral cardiacprecursor pools unite at the midline, cranial to the oropharyngeal membrane toform the primary heart field (PHF), which gives rise to the left ventricle andthe atria. A retinoic acid gradient originating in the posterior mesoderm fatesthese cells to an atrial identity, whereas the more anterior cells not influencedby retinoic acid will become the left ventricle. The secondary heart field (SHF),arising from the pharyngeal mesoderm, localizes adjacent and posterior to thePHF. The SHF will form the right ventricle, outflow tract and inflow myocardium.The identity of the PHF is determined by upstream activators NKX2.5 and GATA4,and that of the SHF is determined by ISL-1 and FOXH-1.

In particular, ISL-1 expressiondistinguishes the PHF from SHF. These upstream activators regulate a core regulatorynetwork of transcription factors (MEF2, NKX2, GATA, TBX and Hand) that will coordinatethe differentiation and patterning of the cardiac tissue. Development of theheart is completed by week 8 to 9. Heart defectshave an incidence of about 1 in 100 live births, representing the most commonclass of congenital malformations. Interfering with the signaling networksinvolved in heart specification will result in a number of malformations thatdepend on the specific gestational time. For example, mutations in NKX2.

5, GATA4,TBX5 result in atrioventricular septal defects. These defects are expected to originatelate in gestational week 4, which is when the early septum I between the leftand the right atria and the muscular interventricular septum appear. Acondition associated with atrial and ventricular septal defects, as well asupper limb malformations, is Holt-Oram syndrome, caused by TBX-5 mutations.3.

Induction is akey process in development.  Describe aninductive event in development.Embryonic induction describes the interactionbetween inducing and responding tissues that results in molecular andmorphological changes in the responding tissue. Induction drives thedevelopment of various tissues and organs in most animal embryos; for example,the eye lens, the nervous system and the heart.

The eye is acomplex structure that starts to develop at day 22 of gestation and involvesectoderm, neural crest cells, and mesenchyme. The major events of eyedevelopment occur between week 3 and week 10. The neural ectoderm gives rise tothe optic nerve, the neural retina, the iris and ciliary body epithelia, thesmooth muscles of the iris, and some of the vitreous humor. The surfaceectoderm gives rise to the lens, the choroid coat and sclera, the conjunctivaland corneal epithelia, the eyelids, and the lacrimal glands.

The remainingocular structures originate from mesenchyme. Formation of these structures are mediatedby induction processes.Formation of theeye lens is a classic example of induction.

The eye lens derives from cells inthe prechordal plate and starts forming during late gastrulation in week 3.Cells in the eye field express RAX and PAX6 as primary factors inducing theoptic vesicle. PAX6 expression in the surface ectoderm allows the underlyingoptic vesicle to respond to inductive signals (FGF and BMP) via SOX2, another importantfactor. This signals the surface ectoderm to thicken and form the lens placode.Through VSX2, the optic vesicles are patterned into the future neural retina,and through MITF and OTX2, into the retinal pigment epithelium.

Inductiveinteractions between the optic vesicle and the lens placode results ininvagination and formation of the lens vesicle by day 28 and the optic cup byday 34. Then, the lens vesicle detaches from the surface epithelium and underthe influence of PAX6 and SOX2 primarily, cells in the posterior part of thelens elongate and differentiate into long, transparent cells called lens fibers.Here, PAX6-induced FOXE3 plays an essential role in the activation of lensfiber genes to give rise to the lens crystalline proteins. In future events,the lens nucleus will form and through successive mitotic divisions andinfluences from the retina, of which FGF is a major component, eye lensdevelopment will complete.             In mammals, disruption of theapposition of optic vesicles and surface ectoderm interferes with lensinduction, resulting in malformations such as microphthalmia (small eye) oranophthalmia (absent eye). Mutations in several human genes, including SOX2 andOTX2 can result in microphthalmia, presumably because the surface ectoderm isunable to respond to the inductive signals originated in the optic vesicle.

Mutationsin the human RAX gene cause anophthalmiaand are usually ascribed to a failure of formation of the optic vesicle.  4. Pleiotropy isthe concept that a mutation in a single gene can cause malformations in multipleorgan systems because those systems use that gene product for theirdevelopment.  Describe a malformationsyndrome that illustrates this principle and how the pathway functions in morethan one tissue or organ.Mutations in the human homologue of the Drosophila eyes absent gene, EYA1, causebranchio-oto-renal (BOR) syndrome, an autosomal dominant condition mainly characterizedby renal abnormalities, various degrees of hearing loss, structural ear defects,and branchial fistulas or cysts. To exemplify the concept of pleiotropy in BOR,the role of EYA1 in kidney and eardevelopment will be described. In higher animals,a network composed of genes belonging to the Pax, Six, Eya and Dach families plays a crucial regulatory role in the development ofmultiple structures including the ears, the kidneys, the heart, the placodesand the pharyngeal pouches, among others. This network is often referred to asthe Pax-Six-Eya-Dach network (PSEDN) and is highly conserved throughout animalevolution.

Eya1 is a key component in this network. EYA1 is expressedin different embryonic structures, including the metanephric mesenchyme of the developingkidney, where it is required for the expression of GDNF, which in turn isrequired to orchestrate ureteric bud outgrowth. Eya1 knockout mice show loss of Gdnfexpression.

However, EYA1 cannot stimulate Gdnftranscription by its own, but requires a member of the Six protein family fornuclear translocation; thus, it is likely that the effect of EYA1 on Gdnf is indirect. Eya1 null mice also show loss of Six1 and Six2 gene expression,suggesting an EYA–>SIX–>GDNF functional cascade in kidney organogenesis.In humans, disordersof the auditory system are usually associated with renal abnormalities whenmutations in EYA genes occur. Invertebrates, the otic vesicle develops from the otic placode and is marked by highexpression of SIX1 and EYA1, both of which are involved in the pathogenesis ofBOR. Eya1-deficient mice lack ears,which highlights the importance of this gene in ear formation. Hypomorphicmutations of the Eya1 gene result ininner ear abnormalities and hearing problems in both mice and humans. Inaddition, EYA1 and SIX1 can induce the putative neurosensory stem cells in thecochlea (GER cells) to differentiate into hair cells, while EYA1, SIX1 and SOX2can simultaneously induce GER cells to differentiate into neurons. Therefore, EYA1(along with SIX1) initiates neuronal precursor differentiation in the innerear.