Early Embryology

1. Early Embryology GEMP – 2006 Avinash Bharadwaj

2. Gross Form,Correlation Embryology Cellular and Molecular phenomena Errors in development Structural Molecular (Clinical aspects) Evolutionary mirror Why and How

3. Sexual Reproduction • Vast potential for variation • Basis for evolution • Genes and gene pools • Population genetics • However… • Requires special cells : gametes • Spermatozoa • Ova (Oöcytes) • Overview : • Reproductive system – male and female • Two types of cell division

4. Reproductive System • This overview of the male and female reproductive systems covers their anatomy as relevant to the understanding of early embryology. Anatomical, histological and functional details will be studied in the appropriate block.

5. Seminal vesicle Prostate Ductus deferens Testis Male Reproductive System • The principal organ, testis, produces male gametes or spermatozoa. A spermatozoon is cell with very little cytoplasm and nucleus forming its head, a neck with a single, long, spiral mitochondrion and a tail. • Spermatozoa produced by the testis are carried by a tube, the ductus deferens to the pelvis where glands add their secretions, forming semen. Semen is ejaculated through the penis and deposited in the female reproductive system.

6. Uterine tube A B Ovary Uterus C Vagina Female Reproductive System • The ovary produces the female gametes. • The uterine tube (also known as the oviduct or Fallopian tube) transports the ‘conceptus’ (product of fertilisation) to the uterus. • The uterus houses the embryo / foetus until birth. The vagina is the ‘birth canal’. • Some of the terms used here are explained in the next slide.

7. Gamete, Conceptus, Embryo, Foetus • The female gamete is often called the ovum. In reality, it is released from the ovary and before it can truly be called ‘ovum’. The fertilised gamete is sometimes called zygote. The unicellular zygote undergoes significant changes by the time it reaches the uterus. • From an undifferentiated single cell the new human reaches a stage where most of the body systems are established in form and some achieve partial functionality. This part of its life is the embryonic phase (explained again later!). Thereafter, its intrauterine life is dominated by phenomenal growth – this is the foetal stage. • We now take another look at the reproductive organs in the female.

8. Uterine tube * * A B Ovary Uterus C Vagina Female Reproductive System • The uterine tube has a funnel-like end facing the ovary, called the infundibulum (meaning a funnel!). The fronds forming its border are the fimbriae. • The somewhat dilated portion (*) towards the uterus is the ampulla, followed by the narrow part leading to the uterus. Due to the thickness of the uterine wall the last part of the tube is actually within the uterine wall (intramural part). • The uterus has three parts – the fundus (A) at the top, the large body (B) and the cervix [‘neck’, (C)] at its junction with the vagina.

9. Cell and Cell Division • Some familiarity with cell biology especially with reference to the nucleus is presumed here. Some important concepts : • Chromatin : Coloured (when stained!) material in the nucleus, comprising nucleic acids and proteins. • Chromosomes : supercoiled DNA with proteins, arranged as ‘coloured sticks’. Chromosomes are visible as discrete structures only during cell division. Each chromosome has two ‘arms’, short and long, with a small enlargement, the centromere, between the two. • All nucleated cells in the human body, with the exception of the final stages of gametogenesis, have 23 pairs of chromosomes in their nuclei. Two members of a pair are known as homologous chromosomes. In each pair, one chromosome is paternal, one maternal. • One pair of chromosomes (#23, X + Y) is designated sex chromosomes. Males have X + Y, females have X + X. • A cell with 23 pairs of chromosomes is described as diploid; one with 23 single chromosomes is termed haploid. • The genetic material in the nucleus of a cell undergoes ‘replication’ before cell division. This phase in a cell’s life is designated the ‘S’ phase (‘s’ for synthesis). After the S phase there is a quiescent period followed by cell division.

10. Cell and Cell Division • All body cells that can divide, with the exception of a stage of gametogenesis, divide by ‘mitosis’. Mitotic cell division produces two daughter cells which are genetically identical with the parent cell. • During gametogenesis, there is a stage when a two-stage division produces four haploid daughter cells. This is meiosis or meiotic division, also called a reduction division. However, there is more to meiosis than mere reduction to the haploid state. • The following slides present the phenomena associated with chromosomes during cell division. Details of the stages of cell division do not feature in these. The focus is on nuclear events, cytoplasmic details are not shown. • A few more terms and concepts will be introduced in the course of the description.

11. Mitosis The chromosomes have replicated prior to division, but not yet seen as discrete structures. The nuclear envelope is intact.

12. Mitosis A B In each pair, there is one maternal chromosome and one paternal. A chromosome, when fully condensed may be shown as in ‘A’. It has two identical halves called chromatids, shown at ‘B’. The most important point to be understood here is that each chromosome has replicated. A chromosome in a non-dividing cell is a chromatid, if at all we could see it! Only two chromosome pairs are shown in the nucleus in these pictures. One pair is shown in pink, one in blue. They are still being condensed.

13. Mitosis During metaphase, the chromosomes are arranged along a plane in the middle of the cell (‘equatorial plane’). A ‘spindle’ of microtubules (mitotic spindle) attaches the chromosomes to the centrosomes. Shortening of the microtubules separates the chromatids. The chromatids (chromosomes of the daughter cells) migrate towards the poles of the dividing cell.

14. Mitosis The cytoplasm divides to create two roughly equal cells. Note how the chromosomes ‘disappear’.

15. Meiosis The picture at top left shows the cell resting after the replication of chromosomes. Once again we see two representative pairs of chromosomes (bottom). In each pair, paternal and maternal chromosomes are shown in different colours. Meiosis is a two-stage division. The two stages are often called meiosis I and meiosis II. We are looking at meiosis I.

16. Maternal : Paternal : Meiosis Homologous chromosomes are arranged next to each other lengthwise. Their corresponding arms cross at a number of points. These points of crossing are called chiasmata. At these points of crossing, homologous chromosomes exchange segments. When this exchange is complete, the two homologous chromosomes cease to be what they were. Each one has segments from both parental chromosomes. The possibilities of chiasmata formation are virtually unlimited. Every cell undergoing meiosis therefore, can give rise to a unique combination of resultant chromosomes.

17. Meiosis Separation of chromosomes now follows a different pattern. Chromatids do NOT separate. One entire replicated chromosome from each pair moves to one pole of the cell. At the end of meiosis I, the two resultant cells are thus haploid, containing one member from each pair. It is worth repeating that the chromosomes of these cells are NOT identical with those of any of the parents. Each of these cells has genes coming from both parents. Considering that the same process has been followed in every meiotic division in the parents of this individual, there has been a great mixing of grandparental genes as well!

18. Meiosis The cells begin the second division soon, without an S phase. Recall that each of these cells is haploid and the chromosomes are replicated. In meiosis II, the chromatids of these chromosomes separate. On the right, we see the beginning of the formation of four cells.

19. Meiosis At the end of meiosis therefore, four unique, haploid cells are formed.

20. Gametogenesis • In both sexes, a pool of cells destined for gametogenesis is set aside during embryonic life. • During gametogenesis, these cells divide by mitosis first, to retain a pool of cells. • Essentially, some of the products of these mitotic divisions must undergo meiosis. • The details of the actual process differ in the male and the female.

21. Spermatogenesis In the male, spermatogenic activity begins at puberty. The spermatogenic cells, called spermatogonia undergo mitotic division, whereby some cells remain as spermatogonia and some take the path of meiosis. Each meiotic division produces four haploid cells called spermatids. Spermatids then undergo structural changes – loss of some cytoplasm, formation of a tail. Spermatogenesis is a continuous process.

22. Oögenesis • Process begins during intrauterine life • Meiosis I incomplete, suspended until puberty • During reproductive life : • Each month several oöcytes begin maturation • Normally only one is released (others degenerate) • “Ovulation” • Meiotic divisions highly unequal • Oöcyte and ‘polar bodies’ • Meiosis completed after the entry of a sperm

23. Oögenesis : Implications • Unequal meiotic divisions produce only one gamete with a huge amount of cytoplasm. The polar bodies are small cells, normally unfertilised. • Long suspension of division  probability of abnormal separation of chromosomes – ‘non-disjunction’. • Longer suspension  greater chances of chromosomal abnormalities.

24. Numerical Chromosomal Anomalies – 1 • Non-disjunction can occur in any cell division. It can occur in somatic (non-gametogenic) cells with negligible consequences. Genetically significant non-disjunction may occur during spermatogenesis (paternal) or oögenesis (maternal). In either case, all embryonic cells will have a numerical chromosomal anomaly. • Non-disjunction may occur after fertilisation in an embryo. If it occurs early enough, significant numbers of cells will have an anomaly. These cells are mixed with normal embryonic cells. This phenomenon is called mosaicism.

25. Numerical Chromosomal Anomalies – 2 • Non-disjunction leads to the formation of daughter cells with unequal chromosome numbers – one with three copies of a chromosome (trisomy), the other with only one (monosomy). In general, monosomy is lethal. • The normal diploid number of chromosomes is also called ‘euploid’ (eu = good), a deviation from this number is described as aneuploidy. • The terms trisomy / monosomy refer to a specific chromosome that has suffered non-disjunction, the terms euploidy / aneuploidy refer to the total chromosomal complement.

26. Structural Chromosomal Anomalies • Structural abnormalities do not affect the total chromosome number, but do have serious consequences. • Translocation is an anomaly where a part of a chromosome breaks off and is attached to another. The two chromosomes may even ‘exchange’ equal of unequal segments. • In ‘deletion’ a segment of a chromosome is lost. • Inversion is an anomaly where a segment of a chromosome is detached and reattached in an inverted manner. Though this does not involve loss of genes, the disturbance of their sequence along the chromosome may be significant.

27. The Menstrual Cycle – 1 • The release of one oöcyte every month has functional rationale. • The uterus must be prepared, in anticipation of fertilisation of the oöcyte, for receiving it and sustaining development for the duration of pregnancy. This preparation involves the lining of the uterus (‘endometrium’ = epithelium + supporting tissues). If the oöcyte is not fertilised the prepared endometrium is discarded. Thus there are coordinated cyclic changes in the ovary and the uterus. All these are controlled by hormones. • The histological details of uterus, ovary and those of their hormonal control will dealt with in the reproductive block. At this stage the salient features are mentioned. • During each cycle, as the endometrium matures, it increases in thickness, blood vessels proliferate and glands develop from the lining epithelium.

28. The Menstrual Cycle – 2 The average duration of the cycle of changes is 28 days, though cycles as short as 20 days or as long as 35 days are normal. In the average 28-day cycle, ovulation takes place around day 14. If the oöcyte is not fertilised, most of the endometrium is discarded. This is accompanied by a significant amount of blood loss through the broken blood vessels. The endometrial tissue with the blood constitutes menstrual flow which lasts 3 to 5 days. Menstrual flow is the only reliable external marker of the cyclic changes. The first day of the flow is thus taken as “Day 1” of the cycle, though this in fact marks the end of the previous cycle. It is noteworthy that the interval between ovulation and the next menstrual period is rather constant around 14 days, whereas that between day 1 and ovulation varies according to the length of the cycle in a paticular individual.

29. Zona pellucida Corona radiata Fertilisation • Fertilisation is the union of the male and female gametes. It is pertinent to note that the female gamete has not completed the second meiotic division at the time of release from the ovary, and should be correctly called an oöcyte. In the adjoining picture note that its is surrounded by a thick ‘wall’ called the zona pellucida (‘clear zone’). This is in turn surounded by a layer of supporting cells forming a ‘crown’, the corona radiata. At this stage the zona pellucida also includes the polar body formed at the end of meiosis I (not shown in this picture). • Fertilisation most commonly takes place in the ampulla of the uterine tube.

30. Acrosome Fertilisation At the tip of the sperm head is an enzyme-containing structure called acrosome. Acrosomal enzymes allow the sperm to ‘bore’ through the zona pellucida. The entry of one sperm causes a molecular reaction in the zona pellucida which prevents the entry of any other sperm. The entry of the sperm is also followed by the completion of the second meiotic division and a second polar body is formed. The ovum now has two ‘pronuclei’ male and female. These soon lose their nuclear membranes and a diploid cell is formed, called the zygote. These events are shown in the next slide where the polar bodies are also shown.

31. Fertilisation thus has some ‘consequences’ : • Restoration of diploidy • Chromosomal sex determination • Completion of meiosis II in the oöcyte • Initiation of the first cell division (cleavage)

32. Cleavage, Morula and the Blastocyst • The fertilised ovum or zygote has a very large cytoplasmic volume. During the first few divisions separation of chromatids of replicated chromosomes follows the same pattern of mitosis, but the cytoplasm does not increase. The division of cytoplasm in fact reduces the cytoplasmic volume in daughter cells. • These divisions lead to a group of cells that collectively appear like a mulberry and called as the morula. Soon a cavity appears in the cell mass which now is called the blastocyst. In the blastocyst we see two groups of cells – a smaller ‘inner cell mass’ destined to become the embryo proper and an outlying layer which later forms the tissues that connect the embryo and the foetus to the mother. This cell layer is known as the trophoblast. • The zona pellucida persists almost throughout these stages while the cell mas is slowly propelled towards the uterus by the action of cilia in the epithelium of the uterine tube. • The persistence of the zona pellucida is a factor in preventing the implantation of the embryo in the wall of the tube. This is important as the trophoblast is highly invasive in nature. • These stages are illustrated in the next two slides.

34. Blastocyst • Inner cell mass • Trophoblast • Zona pellucida disappears • Implantation • Implantation is the process of embedding the embryo in the uterine wall. • Disappearance of the zona pellucida and the invasive nature of trophoblastic tissue are the major factors in implantation. • The second picture shows significant changes in the embryo – these are explained in the next two slides.

35. B C F G B A D E Implantation and beyond… • First of all, notice the nature of the endometrium : • A : surface epithelium, B : connective tissue, • C : glands. • Implantation is said to be complete when the surface epithelial layer of the uterus regains its continuity over the embryo. • Trophoblast has now differentiated into two parts: • D : cytotrophoblast – cell boundaries are clear. • E : syncytiotrophoblast – cell boundaries have disappeared. (Syncytium = ‘cells together’). • A part of these trophoblastic masses will form the placenta. • The embryo itself has two layers called the epiblast (F) and the hypoblast (G). • Two cavities appear around the embryo –one on the epiblast side : amniotic cavity, that on the other side is the yolk sac. The epiblast continues as the amnion (an epithelial layer) around the amniotic cavity. The terms epiblast and hypoblast are introduced here to make the description cohesive and complete. The concepts introduced in the next slide are more important.

36. Embryonic disc Embryonic disc, Top view Yolk sac Head end Embryonic disc, Sectioned along this line Primitive streak Trilaminar Embryo In surface view, the embryo appears as a flat disc with the future head and tail ends established. At the tail end, cells of the epiblast begin to migrate as indicated by the curved arrows in the sectional view below. The site of this migration is seen as the ‘primitive streak’. This migration establishes the final three layers of the embryo – ectoderm, mesoderm and endoderm (entoderm). The core concepts here are : 1. From the inner cell mass, a trilaminar embryo emerges. 2. The amnion is continuos with the ectoderm and encloses the amniotic cavity. The hypoblast is replaced by the endoderm and the yolk sac also changes its nature. However, you may overlook this detail!

37. Ectoderm * Entoderm Notochord & Neural Tube Continuing with the sectional view in the last slide… In the upper figure observe the three germ layers the colours of their labels match their representations. The mesoderm is unlabelled. In the centre is a cordlike structure, the notochord (*) that runs length wise through the embryo. This is the notochord – it is the ‘axis’ of bilateral symmetry of the embryo. In the middle figure a groove (blue arrow) formed by a specialised area (between the red lines) of the ectoderm is shown. This grove is the forerunner of the nervous system. The lips of this groove approximate to form a tube, the neural tube. The lips of this groove (arrows in the third figure) form the neural crest. Soon, the neural crest and tube will be internalised with the rest of the ectoderm becoming a continuous layer over it. Changes are taking place in the mesoderm as well, these are described next.

38. Amniotic cavity Ect x x Yolk sac Ent Divisions of Mesoderm A huge bulk of body tissues arises from the mesoderm. These are listed a little later. The salient feature illustrated here is the division of this layer into three parts. The notochord is indicated by the black arrow. Just next to the notochord (the axis!) is a mass of mesoderm called paraxial mesoderm (blue arrow). This is a somewhat cylindrical mass stretching along the length of the embryo. On the extreme lateral side is a plate-like mass, the lateral plate mesoderm. The not-so-well-defined mass in between the two is the intermediate mesoderm. The lateral plate mesoderm shows a clear split enclosing a cavity (x). This is the forerunner of a great system of cavities in the body, the coelom. This will be described much later. At this stage just note that one ‘wall’ of the coelom faces the ectoderm, the other faces the endoderm. • You may be wondering why the mesoderm seems to extend beyond the confines of the embryonic plate. Well, there mesoderm outside the plate as well, and this is aptly called extraembryonic mesoderm. • However, for our current purpose, we shall ignore it. • Also ignore the cavity in the paraxial mesoderm!

39. R L Segmentation We are not just symmetrical, we are ‘sliced’ too! The ‘slices of the body are ‘segments’. Though the entire body has a segmental pattern, in the fully formed human there is no outward sign of this. In the embryo, the segmentation is best seen in the paraxial mesoderm. You can see the blocks of tissue on the left and right sides of the central line of the body in the upper picture. These are segments of the paraxial mesoderm. They are called somites. Each somite further differentiates into a sclerotome and a dermomyotome. The root ‘tome’ indicates a cut or a slice, sclero- is hard. A sclerotome gives rise to a mass of bone. Most of the sclerotomes form parts of vertebrae (more later!) Derm- indicates a part of the skin, here it specifically indicates dermis, the connective tissue component of the skin. Myo- indicates muscle. From this it should be clear that each somite gives rise to bone, muscle and dermis of a segment of the body. This concept will of great help in our understanding of the anatomy of the vertebral column, nerves and skeletal muscles of the body.

40. Fate of Germ Layers The ectoderm gives rise to the covering of the body – specifically, the epidermis (not skin!), hair, nails, the epithelium that covers the eye and the glands in the skin. The mesoderm produces almost all muscle and all connective tissue. Needless to say, the body cavities formed by the split of lateral plate mesoderm are lined by epithelium which is also of mesodermal origin. Blood vessels and the cavity of the heart also arise from the mesoderm and their lining epithelium is mesodermal in origin. Parts of the urogenital system develop from the mesoderm as well. It is pertinent to note here that almost all skeletal muscle comes from somites (special cases will be mentioned later!). The urogenital system has parts which originate from the intermediate mesoderm. Note that this listing aims to give a comprehensive description, some of these points will be reinforced when we deal with the development of individual systems. The endoderm, like the ectoderm, has limited derivatives – it forms the lining epithelium of the digestive system and its glands. How does the flat entodermal layer give rise to the tubular digestive system…?

41. Cardiogenic area 1 Yolk sac Yolk sac Yolk sac 2 3 4 Head, Tail and Lateral Folds In the pictures below, the mesoderm is not shown. These are sagittal sections of the embryo. The ectoderm is blue, entoderm yellow. In the first picture, the head end is indicated by the red (cardiogenic) area that will form the heart. The entire thickness of the embryo begins forms folds at the head and the tail ends. In successive pictures, observe how the endoderm forms a tube, the yolk sac communicates with this tube via a progressively narrowing structure and how the heart ‘descends’ to its final position. In the transverse section, similar lateral folds complete the formation of the embryo that resembles the three dimensional human being. Further details are described with the development of individual systems.

42. Salient Landmarks • We now attempt to place some of these events on an approximate timescale, bearing well in mind that there are bound to be a few variations. • We might as well consider the beginning of this story at the moment of ovulation. Both the sperm and the oöcyte have a finite period of viability. The oöcyte degenerates after a day or so from ovulation if not fertilised, the sperm lives for about three days. We might say that in the ideal case fertilisation takes place within 12 to 24 hours of ovulation. • By 30 hours the first division is complete (two cell stage). • 12 to 16 cells are seen by the third day, and in 4 days a well-formed morula is in the uterine cavity. • By day 5, the blastocyst stage is evident and the zona pellucida has disappeared (also described as the hatching of the blastocyst!). • Implantation begins by day 6 and is completed between days 8 and 10. • Between the 14th and 18th day we see the appearance of the primitive streak and the formation of the trilaminar embryo. • By the end of the third week the formation of the neural tube is well established and somites begin to appear. • This timeline is not intended for memorising individual dates! Some key concepts emerge from this account. These are elaborated next.

43. Some Clinical Correlates A key event of great concern from the mother’s point of view is the time and site of implantation. Though we have considered ovulation as the starting point of the story, subsequent events are more accurately timed as after fertilisation. When the conceptus reaches the blastocyst stage, the zona pellucida disappears and the invasive activity of the trophoblast begins. If this happens before the embryo reaches the uterus, implantation occurs in the tube. The tube is not equipped to handle the growing embryo. Implantation in the tube therefore invariably causes rupture of the tube or the death of the embryo. In the latter case the dead embryo is simply aborted, but the rupture of the tube is a potential emergency. In rare cases implantation may occur on the surface of the ovary or even in the peritoneal cavity (the oöcyte is released in the peritoneal cavity whence it is picked up by the fimbriae of the tube). In exceptional cases a peritoneal implantation may even reach full term. The commonest (and the ideal) site of implantation is the fundus or the upper part of the body of the uterus. In this case the trophoblast forms a placenta which is attached to the same part of the uterus. Too late an implantation may occur in the lower part of the uterus, in which case the placenta may be placed across the inner opening of the cervix. Distention of the uterus in the later part of pregnancy may cause premature separation of the placenta with bleeding that threatens both the foetus and the mother.

44. The Developing Human – Three Phases The total period of intrauterine development can be divided into three parts. • What we have described so far establishes the background for further development. This is the period embryogenesis or early development. At the end of this period all somites have formed and begun to differentiate into masses of segmental muscles or parts of the vertebral column. • From here onward, until about the 12th week the major organ systems of the body are established. This is the period of organogenesis or embryonic period. It must be stressed that this period has no definite end-point, as different systems reach their final form at slightly different points in time. Not only this, different systems reach different stages of functionality during intrauterine life. In general it can still be said that this period is one of great vulnerability. A large variety of substances, infectious agents and physical entities like radiation can damage the embryo, leading to defective development or even death. Each organ system also has its own critical period when it is most vulnerable. Teratology, the study of harmful agents (teratogens) and their effects is a major area of concern and research. • After this period, intrauterine development is marked by phenomenal growth of an almost human form. This is the foetal period and is the longest part of prenatal development.

45. Age of Embryo and Foetus The developing human truly begins its life at the moment of fertilisation. However, this event cannot be recognised clinically. Ovulation is another landmark, but has the same drawback, though there are methods with a fair degree of accuracy. The only event that has an external manifestation is menstruation. • Fertilisation age : this criterion is most useful in embryolgical studies. Events in early embryology are often described with reference to fertilisation. • Ovulation age. Despite its drawbacks this criterion is sometimes used in embryology. • Descriptions of embryos sometimes also mention the number of recognisable somites, as the paraxial mesoderm follows a sequence of somite formation from the head end to the tail end. • Researchers in embryology also follow a system staging of the early embryo. • Clinically the most widely used reference point in time is the first day of the menstrual period preceding ovulation, as menstruation stops during pregnancy. The average duration of a normal pregnancy from the ‘last menstrual period’ (LMP) is 280 days. It must be noted that this is variable and that very few babies are born on the 280th day! Based on the date of the LMP, the estimated date of delivery (also called the expected due date or EDD) can be calculated as 9 (calendar) months and 9 days after the LMP. It convenient to count weeks rather than days or months, and the duration easily translates to 40 weeks.

46. Multiple Pregnancy • Sometimes more than one oöcyte is released at ovulation. If these are fertilised the result is twinning or multiple pregnancy. (For descriptive convenience we shall discuss twins rather than multiple pregnancies). It must be remembered that each oöcyte is genetically unique. Twins born of two different oöcytes are no more or no less similar than any pair of siblings and may be of different sex. Such twins are called dizygotic (binovular) twins. • As cleavage proceeds the cells of an embryo become less capable of developing into a full human. However, the first division cells may proceed on their individual tracks as two separate embryos. The resultant twins, born of a single event of fertilisation are called monozygotic or uniovular twins. They are genetically identical and are of the same sex. Splitting of an embryo may occur as late as the blastocyst stage,in which case they may share an amniotic cavity and / or placenta. • Conjoined twins (‘siamese’ is a term of the past and is not considered either elegant or desirable now!) are formed when a single embryonic mass gives rise to two populations of cells at a slightly later stage. Usually a splitting of the primitive streak is involved.

47. Beyond Early Development… As we proceed through further system blocks, we shall deal with further development of individual systems. It is interesting to note that even during development, the functionality of some systems (CVS) is essential for maintaining the embryo / foetus, some systems (CNS, Kidneys) show physiological activity which is essential to a variable degree and some become functional only at birth (respiratory). The degree of differentiation and specialisation involves acquisition of specific histological features (histogenesis) and in the case some organs (lungs, bones) histological development is carried well into postnatal life. Much as we shall focus on the ‘embryonic period’, clinically the foetal period is of considerable importance. Similarly, in our current discussion we have but mentioned aspects of trophoblastic specialisation (placenta). Full details of these aspects are beyond the scope of the current discussion. Not too long ago embryology was also called ‘developmental anatomy’. This science has now breached barriers between disciplines and progressed into the realm of molecular biology and genetics. Well, for the moment we have to draw a line and wait for the exciting aspects of human development! Last slide!