Embryologi, instuderingshjälp

## Några termer och begrepp

**Utvecklingen** delas upp i tre perioder. De första två veckorna kallas **preembryoperioden** (groddperioden eller blastemperioden), de följande sex veckorna **embryoperioden** och resten av graviditeten **fosterperioden** (fetalperioden).

**Preembryoperioden** karakteriseras av att det befruktade ägget delar sig och att cellerna som bildas förflyttar sig (migrerar). På så sätt bildas en omkring millimeterstor groddskiva med tre lager av celler (groddblad). Dessa tre groddblad (ektoderm, mesoderm och endoderm) är utgångsmaterialet för bildandet av kroppens alla vävnader och organ.

**Själva uppbyggnaden** av kroppen sker under embryoperioden. När den är slut har groddskivan övergått i ett fullbildat embryo med en längd av ungefär 3 cm från huvud till rumpa. Embryot är en människa i miniatyr, och resten av fosterutvecklingen, dvs. fosterperioden, används för tillväxt och träning av kroppen – när barnet föds måste det kunna röra sig, och de inre organen måste fungera.

**blaʹstula**: (latinsk diminutivform av grekiska blastoʹs ’grodd’, ’knopp’), det stadium av ett befruktat äggs utveckling då den genom upprepad celldelning uppkomna cellklumpen, morulan, omvandlats till en vätskefylld blåsa. Blåsans hålighet kallas blastocel.

**blastoceʹl**: (av grekiska. blastoʹs och koilos [kɔiʹ-] ’ihålig’, ’urholkad’)

**ektodeʹrm** (nylatin ectodeʹrma, av ekto- och grekiska deʹrma ’hud’), ektoblast, det yttre groddbladet i djurembryot, ett cellskikt som bildar embryots yttre avgränsning och som differentieras till den färdiga *individens hud och nervsystem.* *Mjölkkörtlar, svettkörtlar och andra hudkörtlar* bildas också från ektodermet, liksom *hår, naglar,* hovar, hornslidan hos slidhornsdjur, fåglarnas fjädrar och kräldjurens fjäll (vilka dock kan stödjas av benplåtar och liknande) samt *munhålans epitel och **tändernas emalj*****.** Ektodermet ger även upphov *till delar av sinnesorganen: luktslemhinnan, smaklökarna, ögats lins och hinnlabyrinten i innerörat*.

**mesodeʹrm:** (nylatin mesodeʹrma, av meso- och grekiska deʹrma ’hud’), det mellersta groddbladet i det tidiga djurembryot, ett cellskikt som hos ryggradsdjur ger upphov till *bl.a. muskler, blod och bindväv.*

**endodeʹrm:** (av endo- och grekiska deʹrma ’hud’, ’skinn’), entoderm, det inre groddbladet i det tidiga djurembryot, ett cellskikt som bildar den färdiga individens *tarmepite*l, hos ryggradsdjur också bl.a. luftstrupe och lungor, lever, bukspottkörtel, sköldkörtel, thymus, urinblåsa och urinrör samt slida. Endodermet är ett cellförband som kan vara kompakt, ihåligt eller i form av en platta. *Vissa endokrina celler är endodermala*, och embryonalt endoderm ingår i *gulesäcken och allantoïs*.

**mesenkym:** [-ky:ʹm] (nylatin meseʹnchyma, av meso- och grekiska eʹnchyma ’vätska’, ’lösning’), *primitiv vävnad som under fosterutvecklingen bildas från mesodermet* och som hos ryggradsdjur *så småningom ger upphov till dels kroppens stödjevävnader*, det vill säga *bindväv, brosk och ben jämte muskler, dels några organsystem, bland annat blodkärlssystemet, urinorganen och könsorganen*.

**splanchnicus:** splaʹnchnicus (nylat., av grekiska splanchnikoʹs, av splaʹnchna ’inälvor’), splanknikus, anatomisk term: som hör samman med de inre organen, t.ex. nervus splanchnicus, en autonom nerv som försörjer delar av bukorganen.

**visceraʹl:** [-ke-] (medeltidslat. visceraʹlis ’inre’), som har samband med de inre organen (viscera), främst i bukhålan

## Development

* Fertilization: 12-24 hours after ovulation
* First mitotic division
* Two cell stage: 30 hours
* Morula stage: 3 days (72 hours)

* Early blastocyst stage: 4-4.5 days :
* disappearence of the zona pellucida
* blastocyst = blastocele + embryoblast + trophoblast (epithelial wall of blastocyst)

* Early phase of implantation: 6 days

## First week of embryonic development: blastocyst and its components

Fertilization occurs 12-24 hours after ovulation. Sexual reproduction is production of offspring involving the fusion of ***haploid cells*** (***gametes***). It does not even have to involve coitus/copulation (IVF). Somatic cells are diploid = 46 chromosomes and are genetically identical. ***Gamets*** are haploid sex cells 23 = chromosomes and they are genetically ***unique***. **Diploid cells are a result of mitosis and haploid from meiosis**. Fertilization occurs when two haploid gametes join to become a cell with 46 chromosomes with 23 chromosomes from each parent. The fertilization takes place (under normal circumstances) in the uterine tube. The sperm has travelled from the vaginal canal and passed the uterus to encounter an egg in the uterine tube and one sperm cell (spermatozoon) has penetrated the egg.This is quite a complex process and it includes such steps as capacitation and acrosome reaction. This first cell is called a **zygote.**

The Fallopian tubes, also known as oviducts, uterine tubes, and salpinges (singular salpinx), are two very fine tubes lined with ciliated epithelia, leading from the ovaries of female mammals into the uterus, via the utero-tubal junction.

When follicles begin to mature surrounding follicular cells proliferate to produce a stratified epithelium of granulosa cells, and the unit is called a primary follicle. Granulosa cells and the oocyte secrete a layer of glycoproteins on the surface of the oocyte, forming the ***zona pellicuda***.

**Phases**

* pre-embryonic: 1-(2)3 weeks
* embryonic phase: 4 – 9 weeks
* fetal phase: after 9 weeks to birth

**Pre-embryonic**

The ***zygote*** is the **first somatic cell** of the baby to be. After fertilization it takes about 30 hours for the zygote to divide in to two cells. After that it takes about 24 hours for the two cells to become 4. Then it takes about 12 hours for it to become 8. The time interval shortens for each division. These cells, which become smaller with each cleavage division, are known as blastomeres.

* **After about 3 days the cells have become 16 and are know called a *morula* (latin for mulberry)**.
* Inner cells of the morula constitute the **inner cell mass,** and the **surrounding cells compose the outer cell mass**.
* The ***inner cell mass*** gives rise to **tissues of the embryo proper** and **the outer cell mass forms the trophoblast, which later contributes to the placenta.**
* Day 4 - the number of cells have passed 58 and the baby to be is now called a ***blastocyst*** (*blast = nutrition cyst = closed sac*).

The ciliated cells in the fallopian tube moves the blastocyst towards the uterus. It takes about a week. About the time the morula enters the uterine cavity, fluid begins to penetrate through the zona pellicuda into the intercellular spaces of the inner cell mass. Gradually, the intercellular spaces become confluent, and finally, a single cavity, the blastocele, forms. The inner cell mass is now called the embryoblast and they are concentrated at one pole. The outer cell mass is called trophoblast. The zona pellicuda has disappeared, allowing implantation to begin.

In the uterus the ***blastocyst* implants in the endometrius**, the uterine mucosa, this process is called implantation. New studies suggest that L selectin on trophoblast cells and its carbohydrate receptors on the uterine epithelium mediate initial attachment of the blastocyst to the uterus.

At first the baby to be gets its nutrition from the egg where nutrition is stored for that purpose. After implantation the blood vessels in that lining of the endometrius provides nutrition.

**zygot → morula → blastocyst → embryo → fetus**

**trophoblast - "näringsknopp/grodd" - kommer att bli fosterhinnor och moderkaka**

**blastocele - "ihålig knopp/grodd"**

**blasocyst - "knopp/groddblåsa"**

**embyoblast - "fosterknopp/grodd" - kommer att bli själva fostret**

## Second week of embryonic development: The *bilaminar germ disc*

2 veckor, två lager

The ***morula*** consists of identical cells, but as it becomes the ***blastocysts*** the cells start to differentiate.

### **Inductive mechanisms during embryonic development**

***Embryonic induction (EI)*** is **fundamental to the formation of tissue diversity.**

***EI*** is defined as the stimulation of a **specific developmental pathway** in one **group of cells** (*the responding tissue*) **by** a closely **approximated group of cells** (*the inducing tissue)*.

**Ex:**

1. *Development of the vertebrae is induced by the notochord and the neural tube.*
2. *Reciprocal epithelial-mesenchymal inductions during organogenesis.*

Embryonic induction involves signaling molecules, transcription factors, and extracellular matrix components.The inductive cascade results in the activation of the genes characteristic of the differentiated responding tissue.

### **The blastocyst**

The ***blastocyst* is hollow,** the cells are condensed to the ***embryoblast.* *Trophoblasts*** are **cells forming the outer layer** of a blastocyst, which provides nutrients to the embryo, and develops into a large part of the placenta. ***Trophoblast*** (*trophēʹ ’näring’ och blastoʹs ’grodd*) will become the chorionic sac and the placenta (yttre fosterhinnan, (korion) och moderkakan). Villous trophoblasts have **two cell populations:** ***undifferentiated cytotrophoblasts*** and fully ***differentiated syncytiotrophoblasts***. Trophoblasts are characterised by **villous structures**. Cells of the cytotrophoblast proliferate locally and penetrate into the syncytiotrophoblast, **forming cellular columns** surrounded by syncytium. Cellular columns with the syncytial covering are known as **primary vili.**

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### **Trophoblast over the embryoblast becomes:**

* The **inner layer** of the **trophoblast** becomes ***cytotrophoblast*** (översatt betyder det "cellnäringsgrodd") at the area where the blastocyst is implanted in the endometrium wall. It gives rise to the **outer surface and villi of the chorion (yttre fosterhinnan)**. Also called **Langhans' layer**.

* the ***syncytiotrophoblast*** (översatt ungefär med- eller "sammancellnäringsgrodd") is a continuous, specialized layer of **epithelial cells**. They cover the entire surface of villous trees and are in direct contact with maternal blood. Syncytiotrophoblasterna borrar sig in i epitelet i livmoderväggen. Syncytiotrophoblastlagret bildas genom att cellerna i lagret förlorar sitt cellmembran och bildar en cytoplasmatisk massa, vilken invaderar cellväggen och bryter ner cellerna de får kontakt med. Detta görs i syfte att blastocysten ska kunna sjunka in i livmoderväggen. Därefter täcks den genom en delning av yttre livmoderceller, vilka växer över blastocysten. Syncytiotrophoblasterna kommer också (runt dag 10-11) att forma speciella hålrum (blodlakuner). Syncytiotrophoblasterna "invaderar" moderns blodkärl och moderns blod tillåts att flöda i lakunerna. Detta är viktigt då det utgör förstadiet till, eller - **den primära moderkakan**. (Överkurs; syncythiotrophoblasterna har inga HLA-molekyler, vilket alltså gör att mammans blod inte reagerar immunologiskt på den främmande kropp som ju faktiskt fostret är.)

Fully developed terminal villi are the functional unit of maternal-fetal oxygen exchange and nutrient transport.

At the **end of 2nd week: primitive utero-placental circulation**. (Around day 11-12.)

**The embryoblast differentiates into:**

* ***the epiblast*** - that will form the **amniotic cavity** (amnion) **and are the cells that will give rise to the embryo**. Epiblasterna kommer på ryggsidan av embryot att bilda amneoblaster som kommer att bilda amnion som från början är en tunn liten hinna, men som sedan kommer att blir den innersta fosterhinnan och omsluta hela fostret. High kolumner cells.

* ***the hypoblast*** also called the **primary endoderm** - **will form, among other things, the umbilical cord.** Från magsidan av embryot kommer hypoblaster att bilda celler som löper ut och som kommer att bli bland annat gulesäcken. Small cuboidal cells.

The hypoblast is a thin monolayer of small cuboidal cells that make up the lower layer of the bilaminar embryonic disc. This layer can be distinguished from the overlying epiblast in the embryo as early as day 7.

## Third week of embryonic development - the trilaminar germ disc

Tre veckor, tre lager

* **Gastrulation**
* **Trilaminar germ disc**
* **Initial development of the somites and the neural tube**

**Gastrulation**

Gastrulation (nylat., bildning med ett latin diminutivsuffix till grekiska gastēʹr ’mage’) is the process in which the ***ICM*** (inner cell mass) in converted into the ***trilaminar embryonic disc***, which is comprised of the ***three germ layers*** (groddlager):

* **Ectoderm/ Ektoderm** ("outer skin"): Skapar hjärnan och nervsystem samt det yttre hudlagret med hår och naglar och faktiskt tändernas emalj.
* **Mesoderm** ("middle skin"): Bildar allt övrigt.
* **Endoderm** ("inner skin"): Bildar epitelcellerna i matsmältnings, andnings- och genitalsystemet, samt körtlar associerade till dessa.

### Primitive Streak

**Formation** of the ***primitive streak (PS)*** marks the **first event of gastrulation**. The **primitive streak** is a **linear band of thickened epiblast** that first appears at the **caudal** end of the embryo and **grows cranially**. It appears as an **elongating groove** (***primitive groove***) on the (dorsal midsagittal) **surface of the epiblast** along the anterior-posterior axis of the embryo. At the **cranial end** its cells proliferate to form the **primitive node**(**primitive knot)**. With the appearance of the ***primitive streak*** it is possible to distinguish cranial (primitive knot) and caudal (primitive streak) ends of the embryo.

**Primitive node**

The primitive node is a signaling structure that initiates the notochordal formation and decides left and right in the embryo. Its cilia directs **TGF-beta,** **Shh** and **FGF8** (among other) to the left side.

**Molecular basis**

* The ***PS*** is induced by ***Nodal, a*** **TGFβ family member.** (*Transforming growth factor beta (TGF-β) is a secreted protein that controls proliferation, cellular differentiation, and other functions in most cells. It is a type of cytokine which plays a role in immunity, cancer, bronchial asthma, lung fibrosis, heart disease, diabetes, Hereditary hemorrhagic telangiectasia, Marfan syndrome, Vascular Ehlers-Danlos syndrome, Loeys–Dietz syndrome, Parkinson's disease, Chronic kidney disease, Multiple Sclerosis and AIDS.*)

* **After** ***PS*** formation, **Nodal** (produced by the node = anterior-most part of the PS) **induces genes necessary** for **formation** of **dorsal and ventral mesoderm and head (anterior) and tail (posterior) components.**

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The rostro-caudal (**rostro**(i sammanhanget) =*cecal, cranial, åt huvudet till*, **caudal**(cauda = svans)*beläget åt svansen eller svanskotan till, motsatsen till rostral*) and medial-lateral axes of the embryo are**defined by the primitive streak**. The **rounded *primitive node****,* or ***Hensen's node***, is situated at the **cranial tip of the primitive streak**, and contains a depression called the ***primitive pit.*** The **primitive pit is continuous** with the primitive groove. It is the ***primitive node*** that controls the ***gastrulation process.***

* **Cells from the epiblast** **migrate** into the **interior of the embryo**, **via** the ***primitive streak***, in a process termed ***invagination,*** which involves a cellular ***epithelial-to-mesenchymal transition (EMT)***. The initial **wave of migrating cells** streams through **the primitive streak**, **displacing the *hypoblast*** cells to **become the *definitive endoderm*,** which ultimately**produces the future gut derivatives and gut linings.**

* The**second wave** of migrating cells **populates a layer between the *epiblast* and the definitive *endoderm***, thereby forming the ***mesoderm layer.*** *The order in which they are finally arranged are: on top ectoderm, in the middle mesoderm and on the bottom endoderm.*

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Once the ***mesoderm* has formed**, the remaining ***epiblast*** cells **cease to ingress and form the *ectoderm.*** The ***ectoderm* gives rise** to two distinct lineages:

* the ***surface ectoderm***
* the ***neural ectoderm***

### Epithelial to Mesenchymal Transition

Epithelial cells (organised cellular layer) which loose their organisation and migrate/proliferate as a mesenchymal cells (disorganised cellular layers) are said to have undergone an Epithelial Mesenchymal Transition (EMT). Mesenchymal cells have an embryonic connective tissue-like cellular arrangement, that have undergone this process may at a later time and under specific signaling conditions undergo the opposite process, mesenchyme to epithelia. In development, this process can be repeated several times during tissue differentiation. This process occurs at the primitive streak where epiblast cells undergo an epithelial to mesenchymal transition in order to delaminate and migrate.

### Establishment of the body axes

**Establishment of he body axes** takes place **before and during the period of gastrulation.**

As the embryo forms, its overall body pattern is determined by the establishment of three clear axes

* the anterior-posterior axis (head-tail)
* the dorsal-ventral (back-belly) axis
* left-right asymmetry

The establishment of these body axes at the correct time is fundamental to normal embryonic development. For instance, the central nervous system develops along the dorsal surface, with the largest concentration of neuronal tissue—the brain—at the anterior end of the embryo. The limbs develop symmetrically and bilaterally, whereas the heart—although it begins as a symmetrical structure—ultimately comes to point toward the left side of the trunk. Some internal structures are paired (the kidneys, lungs, adrenal glands, testes, and ovaries), whereas many are not (the heart, gut, pancreas, spleen, liver, and uterus).

The anteroposterior axis is signaled by cells at the anterior (cranial) margin of the embryonic disc. This area, the ***anterior visceral endoderm** **(AVE)***, expresses **genes essential for head formation**, including the transcription factors OTX2, LIM1, and HESX1 and the secreted factor cerberus. These genes establish the cranial end of the embryo before gastrulation. The primitive streak itself is initiated and maintained by expression of Nodal, a member of the transforming growth factor β (TGF-β) family. Once the streak is formed, a number of genes regulate formation of dorsal and ventral mesoderm and head and tail structures.

Another member of the TGF-β family, ***bone morphogenetic protein-4*** (BMP-4) is secreted throughout the embryonic disc . In the presence of this protein and ***fibroblast growth factor (FGF)***, mesoderm will be ventralized to contribute to kidneys (intermediate mesoderm), blood, and body wall mesoderm (lateral plate mesoderm). In fact, all mesoderm would be ventralized if the activity of BMP-4 were not blocked by other genes expressed in the node. For this reason, the node is the organizer.

**Anterior-posterior**

* The anterior margin of the bilaminar disc (***anterior visceral endoderm (AVE)*** produces molecules for head induction (TFs: **OTX2, LIM1, HESX1) and Cerberus + Lefty (secreted ).**

**Dorsal-ventral**

* **Bmp4** (embryonic disc) + FGFs: ventral mesoderm + intermediate mesoderm + LPM
* **Dorsal mesoderm (notochord + somites)**are induced following inhibition of Bmp activity by chordin + noggin + follistatin which are secreted by the node.**All mesoderm would be ventralized, and the *neural plate induction*, which is dorsal, could *not take place if Bmp activity* was not blocked by *chordin, noggin and follistatin.***

**Left-right asymmetry**

* FGF8 from the node + PS induces Nodal on the left side
* After neural plate frormation: **FGF8** + **Nodal** (node + PS) and **brachyury (T gene)** are essential for induction of **Lefty-2** in the **LPM** on the **left side.**
* **Lefty-2** + **Nodal** induce **Pitx2** on the left side
* **Lefty 1** from the left side of the floor plate and **Shh from the floor plate + notochord prevent left-side genes** from being expressed on the **right.**
* **Snail is only expressed on the right side**
* Cells of the node have ***cilia*** that direct **Nodal spreading towards the left.**

## neurulation - the forming of the CNS

**Neurulation**

* **3rd wk: *The notochord*** + ***prechordal plate*** + ***endoderm*** induce the nearby, overlaying **ectoderm** to become ***the neural plate***.
* **End of 3rd wk:** Appearence of the **neural folds** and **neural groove.**
* **Day 22:** **Fusion of the neural folds** and formation of the ***neural tube***. Appearence of the neural crest.
* **Closure** of the ***NT*** **proceeds bidirectionally**, **ending** with **closure** of **cranial** and **caudal neuropores.**
* **Day 27:** Completion of neurulation.

**Week three**

**The notochordal process**

Some of the first **cells that migrate through the cranial region of the node** in the midline **form** a structure that is called the **prechordal plate**, it forms **between the tip of the notochord** and the **oropharyngeal membrane**. **Prenotochordal cells** invaginating in the primitive node **move forward cranially in the midline until they reach the prechordal plate**. They form ***the notochordal process*** that has the shape of a hollow tube. Beginning at the cranial midline, the tube elongates, as primitive node cells migrate to the proximal end of the tube. The ***notochordal process*** elongation parallels regression of the primitive streak. On **day 20** of human **development, notochordal process** formation is **complete**.

* ***The notochordal process*** grows cranially until it reaches the ***prechordal plate***, **the future site of the mouth**. **In this area the ectoderm is attached directly to the endoderm without intervening mesoderm.** This area is known **as the oropharyngeal membrane,** and**it will break down to become the mouth**. At the**other end of the primitive streak** the ***ectoderm*** is also **fused directly to the endoderm**; this is known as the ***cloacal membrane (proctodeum), or primordial anus***. The membranes in both these locations will be resorbed during the subsequent development. There the openings for the stomodeum and of the urogenital tract (cloacal membrane) will be located.

* Therefore there is **no mesoderm in the buccopharygeal and cloacal membranes!**

**The notochordal plate**

* **The notochordal process *morphologically*** changes from a hollow tube shape to a flattened plate shape, ***the** **notochordal plate.*** The ventral floor of the notochordal process fuses with the endodermal layer beneath it and thus assumes a flat shape. As the hypoblast is replaced by endoderm cells moving in at the streak, **cells of the notochordal plate proliferate and detach from the endoderm.** They then **form a solid cord** of cells called (the definitive) ***notochord***. It will **underlie the neural tube** and act as a **signalling center** for inducing the **axial skeleton**. This is a transient embryonic anatomy structure, not existing in the adult, required for patterning the surrounding tissues.

**invaginating cells from epiblast → prenotochordal cells → notochordal process → notochordal plate → notochord**

***The notochord*** is thus derived during gastrulation and of **mesodermal origin**. (The cells that migrate via the primitive streak forms the mesoderm.) The definitive ***notochord*** underlies the neural tube and **is a signaling center for inducing the axial skeleton**.

The patterning signal secreted by **notochord cells is sonic hedgehog (shh).** This **secreted protein** binds to receptors on target cells activating a **signaling pathway** involved in the tissues differentiation and development. **These signals are what initiates the forming of the CNS.**

In the **beginning**, the **mesodermal cells build a thin, widely meshed layer on both sides of the median line**, **between the ectoderm and the endoderm.** While the **notochord is forming** - it **grows to the same extent that the primitive streak recedes** - the **intraembryonic mesoderm cells multiply on both sides** of the median line and so **form 3 structures** in the shape of **longitudinal columns.** This process begins at the cranial pole and **continues up to the 4th week** in the caudal direction.

The intraembryonic mesoderm differentiates itself into three subdivisions on both sides of the primitive streak as it recedes:

* **Paraxial mesoderm**
* **Intermediate mesoderm**
* **Lateral plate mesoderm**

**The paraxial mesoderm**

The paraxial mesoblast comes from the epiblast cells that migrated into the region of the primitive node or the cranial portion of the primitive streak. It forms a pair of **cylinder-shaped epithelially-organized mesenchymal segments that are in the immediate vicinity of the neural tube and the notochord**. During the 3rd and 4th week, **these cylinders become segmented** from the cranial end and proceed through the cervical, thoracic, lumbar, sacral and coccygeal regions, into **so-called somitomeres**. Originally, each consists of a pseudostratified epithelium that is arranged around a central cavity, the somitocoel.

**The paraxial mesoderm (somites)**: axial skeleton + voluntary musculature + the dermis of the dorsal skin

**The somites differentiates into:**

* **sclerotome:** cartilage and bone component - vertebrae and ribs
* **myotome:** segmental muscle component - epaxial (dorsal = back) muscles
* **dermatome**: segmental skin component - dorsal dermis

Each myotome and dermatome has its own segmental nerve component

**The intermediate mesoderm**

The intermediate mesoblast is found **between the paraxial mesoblast and the lateral plate mesoblast.** This longitudinal, dorsally lying crest is called the urogenital crest and **serves as the origin of the kidney and gonads**. (**gonaʹd:** *(av grekiska gonēʹ, goʹnos ’avkomma’, ’sperma’, ’könsorgan’), beteckning för könskörtel, dvs. hos honan äggstock, där äggceller och honligt könshormon bildas och hos hanen testikel, där spermier och hanligt könshormon produceras.)*

**The intermediate mesoderm:** urinary system + parts of the genital system

### The lateral plate mesoderm

The lateral plate mesoderm is composed of two thick layers that surround a cavity

* the intraembryonic coelom (the coelom represents the future serous cavity of the trunk: peritoneal, pleural and pericardiac cavities).
* The somatopleure, which is close to the ectoderm, is involved in the formation of the lateral and ventral walls of the embryo. The splanchnopleure, which lies on the endoblast, takes part in the formation of the wall of the digestive tube.

**The lateral plate mesoderm splits into two layers:**

* the splanchnic mesoderm (mesenchyme of viscera)
* the somatic/parietal mesoderm (dermis of limbs + belly/ventral)

both splanchnic + somatic mesoderm form mesothelial membranes

### Genesis of the nervous system week 3-4

With the primary neurulation begins the genesis of the nervous system. The notochord exercises an inductive effect on the ectoblast that lies above it. This causes the ectoblast cells to transform themselves into neuroectoblast cells.

On the 19th day the neural plate appears. It represents the first step in the genesis of the nervous system. The neural plate is identifiable as the medio-sagittal thickening of the ectoblast rostral to the primitive streak. At the cranial end the neural plate is wider and consists of the region where the brain will arise. At the caudal end it is narrower and gives rise to the spinal cord. Approximately 50% of the ectoblast becomes the neural plate and the remainder forms the epidermis.

The neural plate develops in step with the genesis of the notochord, i.e. under the inducing influence of the axial mesoderm lying below it (prechordal plate and cranial portion of the chordal plate). The induction process is very complex, but has its origin in the secretion of inducing factors by axial mesoderm cells. These factors diffuse in the direction of the ectoderm cells that lie above them where they activate genes that are responsible for the differentiation of epithelium that has come from the ectoderm into several rows of prismatic epithelium: the neuroectoblast. In the course of the 3rd week the edges of the neural plate rise up and become neural folds, enclosing the neural groove.

The neural plate has to roll up to form the neural tube. The neural tube that forms will become detached from the ectoderm, but it does stem from it. The neural tube is the precursor for the CNS. The neural folds approach each other after the 25th day and merge to form the neural tube. The closure of the neural tube begins in the cervical area (in the middle of the embryo) and extends from there in both the cranial and caudal directions.

The anterior neuropore (cranial) closes itself on the 29th day. The posterior neuropore (caudal) closes a day later. The top of the anterior neuropore corresponds to the terminal lamina of the adult brain and the posterior neuropore to the terminal filum at the end of the spinal cord.

If the posterior neuropore does not close, a spina bifida occurs. If, on the other hand, the closure of the anterior neuropore fails to take place, an anencephaly results. While the neural tube is in the process of closing, cells on the lateral side of the neural plate detach themselves and form the neural crest.

LPM Fluorescence immunohistochemistry showing migrating NCC (orange)

## Blood and blood vessels (BV)

**Vasculogenesis:** BV arise from **hemangioblasts** ***(Hg)*** /blood islands

**Angiogenesis:** BV sprouting from pre-existing ones

**Origin of Hg:** mesoderm around the yolk sac + lateral plate mesoderm

* **Mesoderm cells become hemangioblasts**
* **Hemangioblasts form BV + blood cells**

## Angiogenesis

Sprouting of vessels from preexisting ones, Also stimulated by VEGF Maturation + remodeling: PDGF + TGFβ : Shh (notochord) + VEGF + Notch + EphrinB2 Ephrin B2 suppresses venous cell fate : Notch + EphB ? Prox1

## Endodermal derivatives

Epithelia of the gastrointestinal tract

Epithelia of the respiratory tract Parenchyma of the thyroid, parathyroids, liver, pancreas Tonsils + thymus Epithelia of the bladder + urethra Tympanic cavity + auditory tube.

## Clinical correlation: Neural tube defects (NTD)

A spectrum of anomalies: mild to severe.

* Spinal dysraphism: failure of part of the NT to close.
* Dysraphism disrupts both the differentiation of the CNS and vertebral arches.
* Vertebral arches are normally induced by the roof plate (induction of Msx2).

### Spina bifida: different types, mild to severe:

* **Spina bifida occulta**: Only failure of fusion of the vertebral arch of a single vertebra. Site marked by a tuft of hair.
* **Meningocele:** dura + arachnoid protrude from the vertebral canal.
* **Meningomyelocele:** neural tissue + meninges protrude.

### More severe forms of NTD

Most severe cases: failure of neural folds to fuse + differentiate + separate from the ectoderm.

* Craniorachischisis totalis: non-closure of the entire NT.
* Exencephaly, anencephaly, craniorachischisis: non-closure of the cranial NT.
* Rachischisis or myeloschisis: analogous defect in the spinal cord.
* Inionschisis: non-closure + non-differentiation of the NT at occipital + upper spinal levels.

### Etiology (causes) of NTD

**Etiology:** genetic, dietary, environmental factors cause NTD.

Teratogens are factors that induce congenital malformations. (**Teratogen:** *[-je:ʹn] (en bildning till grekiska teʹras, genitiv teʹratos, ’odjur’, ’missfoster’, och genes), teratogen faktor, skadlig yttre faktor som stör embryonal- och fosterutvecklingen och framkallar missbildningar av olika slag*.)

* Maternal diabetes, maternal hypertermia (onormalt hög kroppstemperatur som inte beror på infektion eller inflammation), lack of folic acid
* Pax3, Shh, openbrain: important for NT formation.
* Pax3 homozygous mice = spina bifida + exencephaly

## Embryonic folding

**Källor och länkar**

http://media.medfarm.uu.se/play/video/969

http://www.web-books.com/MoBio/Development/06Maxis.html

http://www.embryology.ch/anglais/hdisqueembry/triderm07.html

http://www.uky.edu/~brmacp/oralhist/html/ohtoc.htm

http://audilab.bmed.mcgill.ca/HA/html/oc\_33\_E.html

http://iust.edu.sy/courses/The%20Tooth-Supporting%20Structures.pdf

Amel Gritli-Linde 2012 - föreläsnings PDF:er

Langman’s Medical Embryology

http://www.indiana.edu/~anat550/hnanim/index.html

http://www.indiana.edu/~anat550/genanim/latfold/latfold.swf