Лекция 1 6

1. Лекция 16 Структуры, образованные черепными плакодами или включающие их производные

2. Черепные плакоды образуются из единой преплакодной закладки впереди передней части нервной пластинки (и фланкирующих её границ нервного гребня), а затем сегрегируют на отдельные элементарные плакоды с соответствующими названиями (Gilbert, 2003)

3. Краниальные плакоды эмбриона цыплёнка (стадии 10-13 сомитов) (Schlosser, 2006; 2008)

4. Краниальные плакоды раннего головастика Xenopus. In amniotes, profundal and trigeminal placode are commonly referred to as ophthalmic and maxillomandibular placode of the trigeminal nerve, respectively (Schlosser, 2006; 2008)

5. Схематическое представление морфогенеза и сегрегация эктодермальной черепной преплакоды в различные плакоды у позвоночных (Schlosser, 2006)

6. ГИПОФИЗ (адено- и нейро-составляющие)

8. Локализация гипофиза

9. Образование гипофиза • Anatomically, the pituitary has 2 main parts posterior, or neurohypophysis and anterior, or adenohypophysis (the pars distalis, pars intermedia, and pars tuberalis). Between the two a specialized vascular (portal) system allows communication from the brain to peripheral endocrine organs and other systems. • The pituitary is located within the pituitary fossa of the sphenoid bone, anterior to the lamina terminalis and superior to the pharynx. The shape of the bone surrounding the pituitary led to the naming sella turcica (Latin sella = saddle, turcica = Turkish), as it resembled a saddle shape. • Pit1 (pituitary-specific transcription factor) is a transcription factor important for pituitary development and muations in this gene can lead to abnormalities in pituitary development and hormone production.

10. «Турецкое седло» сфеноидной кости черепа, в которой располагается гипофиз

11. Анатомия головных структур

12. Развитие гипофиза (гистология)

13. Гистология аденогипофизной части

14. Гистология нейрогипофизной части

15. Развитие гипофиза человека • Human Timeline: • Week 4 – hypophysial pouch, Rathke’s pouch, diverticulum from roof • Week 5 – elongation, contacts infundibulum, diverticulum of diencephalon • Week 6 – connecting stalk between pouch and oral cavity degenerates • Week 10 – growth hormone and ACTH detectable • Week 16 – adenohypophysis fully differentiated • Week 20 to 24 – growth hormone levels peak, then decline • Ectoderm- ectoderm roof of stomodeum, neuroectoderm of diencephalon

16. Развитие гипофиза млекопитающего Adenohypophysis – anterior pituitary, glandular (pars anterior, pars intermedia, pars tuberalis) Neurohypophysis – posterior pituitary, nervous (pars nervosa) Adenohypophysis Anterior wall proliferates - pars distalis Posterior wall little growth – pars intermedia Rostral growth around infundibular stem – pars tuberalis Neurohypophysis Infundibulum – median eminence, infundibulum, pars nervosa

17. Транскрипционные факторы преплакоды и плакод

18. Six1/2, Six4/5, and Eya: transcription factors promoting generic aspects of placode development • The panplacodal distribution of Six1/2, Six4/5, and Eya genes and their known effects on development of multiple placodes make these genes the most promising candidates for regulators of generic placodal properties and suggest that their early expression in the pre-placodal ectoderm provides this ectodermal domain with a generic placodal bias.

19. Гены ANF • The ANF homeobox genes (also known as HesX1 or Rpx in mammals) also show anteriorly restricted expression at neural plate stages in the prospective forebrain and in adjacent ectoderm of the anterior neural folds including the prospective adenohyophyseal, olfactory, and possibly lens placodes, but their placodal expression soon becomes confined to the adenohypophyseal placode. ANF genes have been implicated in both patterning and size regulation of forebrain and adenohypophysis and need to be downregulated in order to permit cytodifferentiation of neurons or of several of the adenohypophyseal neuroendocrine cell types. • ANF (HesX1) mutants accordingly show strong reduction or aberrant developmentof the forebrain, adenohypophyseal, olfactory, and lens placodes .

20. Гены Pitx • Pituitary homeobox (Pitx) genes are expressed (with some rather subtle differences between the different paralogues) in the ectoderm immediately rostral to the neural plate including the prospective adenohypophyseal, olfactory, and lens placodes. Besides their function in regulating left–right asymmetries, limb development, and craniofacial development, vertebrate Pitx genes play important roles for adenohypophyseal and lens development. They promote proliferation of different adenohypophyseal cell populations, as well as the expression of various adenohypophysis-specific transcription factors and hormones, and loss of Pitx genes results in reduced expression of many pituitary transcription factors, reduced numbers of adenohypophyseal cells, and in compromised lens development

21. Клетки кармана Ратке дифференцируются в некоторые важные гормон-продуцирующие клетки эндокринной системы. Клетки возникают в пространственно-временной манере. The six pituitary cell types of Rathke's pouch are the: • Corticotropes, which produce proopiomelanocortin (POMC) and cleave it into adrenocorticotropic hormone (ACTH) needed for glucocorticoid synthesis in the adrenal gland • Melanotropes, which produce POMC, but cleave it into melanocyte-stimulating hormone-α (for pigment formation, feeding regulation) • Somatotropes, which produce growth hormone (for cell proliferation) • Lactotropes, which make prolactin (for milk production, uterine contractions) • Gonadotropes, which synthesize lutenizing hormone and follicle stimulating hormone (for gonad growth and development) • Thyrotropes, which synthesize thyroid-stimulating hormone (TSH)for thyriod development

22. Pituitary-specific transcription factor- Pit1 • POU domain, class 1, transcription factor 1 (Pit1, growth hormone factor 1), also known as POU1F1, is a transcription factor for growth hormone. • PIT1 is a pituitary-specific transcription factor responsible for pituitary development and hormone expression in mammals and is a member of the POU family of transcription factors that regulate mammalian development. The POU family is so named because the first 3 members identified were PIT1 and OCT1. of mammals, and Unc-86 of C. elegans. PIT1 contains 2 protein domains, termed POU-specific and POU-homeo, which are both necessary for high affinity DNA binding on genes encoding growth hormone and prolactin. PIT1 is also important for regulation of the genes encoding prolactin and thyroid-stimulating hormone beta subunit by thyrotropin-releasing hormone and cyclic AMP.[supplied by OMIM]

23. Scheme showing Rathke's pouch primordium, wherein corticotropes(arising at embryonic day 12.5) are at the posterior tip; a population of rostral tip thyrotropes (also arising at day 12.5) are at the opposite corner. The most ventral cells are the gonadotropes, followed by the main thyrotropes, the somatotropes and lactotropes, and the melanotropes

24. Extrinsic signals from diencephalon (FGFs, BMPs, Wnt5a) and the oral ectoderm (Shh) specify Rathke's pouch cells through the Lhx3 transcription factor. (Scully and Rosenfeld, 2002).

25. Extrinsic signals from diencephalon (FGFs, BMPs, Wnt5a) and the oral ectoderm (Shh) specify Rathke's pouch cells through the Lhx3 transcription factor. (Scully and Rosenfeld, 2002).

26. Intrinsic signals such as the ventral to dorsal gradient of BMP2 and the dorsal to ventral gradient of FGFs cause the production of different sets of transcription factors along the dorsal-ventreal axis of Rathke's pouch. (Scully and Rosenfeld, 2002)

27. Transcription factors and cell lineage compartments of the anetrior pituitary. The transcription factors are involved with the determination and differentiation of the particular cell types. (Scully and Rosenfeld, 2002).

28. Развитие гипофиза(Summary, paracrine and transcription factors, Xiaoyan Zhu et al., 2007)

29. Ontogeny of signaling molecules and selected transcriptional factors during mouse pituitary organogenesis. Ventral diencephalon (VD), whichexpresses BMP4, FGF8/10/18, and Wnt5, makes direct contact with oral ectoderm and induces the formation of Rathke’s pouch (RP). The opposingdorsal FGF and ventral BMP2 gradients convey proliferative and positional cues by regulating combinatorial patterns of transcription factor geneexpression. Pit1 is induced at e13.5 in the caudomedial region of the pituitary gland, which ultimately gives rise to somatotropes (S),lactotropes (L), and thyrotropes (T). Corticotropes (C) and gonadotropes (G) are differentiated in the most ventral region of the gland. The dorsalportion of the Rathke’s pouch becomes the intermediate lobe, containing melanotropes (M). The infundibulum of the ventral diencephalon growsdownward and eventually becomes the posterior lobe (P) of the gland. The functions of a number of signaling molecules, transcription factors,and cofactors regulating lineage commitment and terminal differentiation of distinct cell types are delineated in a genetic pathway. • Current Opinion in Cell Biology 2007, 19:605–611 www.sciencedirect.com

30. Развитие гипофиза(Summary, paracrine and transcription factors, Xiaoyan Zhu et al., 2007)

31. Дополнение картины развития гипофиза в соответствии с гипотезой Ю. Н. Городилова

32. Схема образования кармана Ратке в результате разрастания мозговых пузырей и краниального изгиба у зародыша цыпленка ( из: Денисьевский и Божок,1973, Jacobson et al.,1979). (а-в) Слева: общий план головы зародыша на разных стадиях эмбриогенеза; справа: расположение прехордальной мезодермы и вентрального края диэнцефалона на различных стадиях краниального изгиба.    (а) Голова зародыша до начала краниального изгиба;    (б) Вентральный поворот мозгового пузыря образует краниальный изгиб головы под прямым углом к зародышевой оси совпадает с началом формирования стенок будущего кармана Ратке.    (в) Краниальный изгиб разворачивает мозг около вентральной плоскости в каудальном направлении и образует складку кармана Ратке.    Br, мозг; D,диэнцефалон; FG,передняя кишка; Inf, инфундибулюм; Ht,гипоталамус; PCM, прехордальная мезодерма; RPE, эктодерма кармана Ратке (оральная ); RP, карман Ратке; N,хорда. Прехордальная мезодерма показана в виде черных овалов.

33. Гипотеза Ю. Н. Городилова(Городилов, 2003, Ж. Общ. Биол.,Т. 64, № 4, С. 318-327). • Вероятно, что участие в формировании гипофиза принимает та часть эктодермы кармана Ратке, которая соединяется с прехордальной пластинкой в области кончика кармана. По всей видимости, секреторная часть гипофиза - аденогипофиз - возникает или прямо из прехордальной пластинки или под ее непосредственным влиянием. Поскольку организатор обладает способностью определять судьбу окружающих клеток или даже переопределять, как это происходит при эктопических пересадках дорзальной губы бластопора, то, очевидно, таким же образом используется эктодерма из района кармана Ратке: она передетерминируется на построение гормональных клеток гипофиза.

34. Гипотеза Ю. Н. Городилова(Городилов, 2003, Ж. Общ. Биол., Т. 64, № 4, С. 318-327) Некоторые этапы развития прехордальной мезодермы и гипофиза.    (а) Стадия нейруляции. Участие прехордальной мезодермы (РСМ) в построении мозга и головы позвоночных. Ряд генов, которые экспрессируются в границах РСМ и влияют на развитие мозга, указаны в скобках.    (б) Стадия вентрализации переднего мозга и образования гипоталамуса. Факторы вентрализации (напр., SHH, BMP7 ) из РСМ влияют на основание мозга; возвратное влияние генов Rpx, T/ebp и др., экспрессирующихся в вентральной части мозга, воздействуют на РСМ.    (в) Замещение РСМ аденогипофизом и появление клеток, секретирующих различные гормоны ACTH, адренокортикотропный; GH, ростовой; TSH, тиреотропный; PRL, пролактин) Ah, аденогипофиз; D, диэнцефалон; Ih, промежуточный гипофиз; Ht, гипоталамус; N, хорда; PBV, портальный кровеносный сосуд; PCM, прехордальная мезодерма ; Ph, задняя часть (нейральная) гипофиза; RP, карман Ратке. Закрашены черным цветом РСМ (а, б) и аденогипофиз (в).

35. Подтверждают гипотезу Ю. Н. Городилова • Ptc2 is expressed in prospective hypophyseal placodal cells and that Shh is expressed in the underlying mesoderm. Moreover, Shh continues to be expressed in tissues surrounding the prospective adenohypophysis, and Ptc2 is expressed in prospective hypophyseal cells. Lim3 and Pax6 are expressed from stage 10 in the prospective hypophyseal placode, whereas Pitx2 starts to be expressed before stage 10. After My Sjödal, Lena Gunhaga: Gene Expression Patterns 8 (2008) 481–485

36. Нейрогипофиз • The Posterior Pituitary Gland consists mainly of neuronal projections (axons) extending from the supraoptic and paraventricular nuclei of the hypothalamus that secrete peptide hormones into the capillaries of the hypophyseal cirxulation. • The neurohypophysis also contains a specialised type of astrocytic glial cells – “pituicytes”.

38. Нейрогипофиз

39. Две доли гипофиза и срединная часть • A few sources include the pars intermedia as part of the posterior lobe, but this is a minority view. It is based upon the gross anatomical separation of the posterior and anterior pituitary along the cystic remnants of Rathke's pouch, causing the pars intermedia to remain attached to the neurohypophysis.

40. Задняя доля гипофиза состоит из: • pars nervosa, or neural lobe, or posterior lobe - region consistutes the majority of the posterior pituitary, and is sometimes (incorrectly) considered synonymous with it. Notable features include Herring bodies and pituicytes. • infundibular stalk - Also known as the "infundibulum" or "pituitary stalk". The term "hypothalamic-hypophyseal tract" is a near-synonym, describing the connection rather than the structure. • median eminence-This is only occasionally included as part of the posterior pituitary. Other sources specifically exclude it from the pituitary

41. Нейрогипофиз (задняя доля гипофиза)-posterior part (PP) • PP is of neural origin and arises from the infundibulum, a ventral evagination of the floor of the diencephalon, which establishes intimate contact with Rathke's pouch that is essential for normal development and function of the AP. The PP is devoid of hormone-producing cells, but instead contains the axonal projections from the hypothalamic nuclei, which produce the hormones oxytosin (OT) and vasopressin (ADH).

42. Гипаталамо-гипофизарная ось

43. Гормоны нейрогипофиза • Hormones known classically as posterior pituitary hormones are synthesized by the hypothalamus. They are then stored and secreted by the posterior pituitary into the bloodstream • Oxytocin is a mammalian hormone(nonapeptide) that also acts as a neurotransmitter in the brain. • It is best known for its roles in female reproduction: it is released in large amounts after distension of the cervix and vagina during labor, and after stimulation of the nipples, facilitating birth and breastfeeding, respectively. Recent studies have begun to investigate oxytocin's role in various behaviors, including social recognition, bonding, anxiety, trust, and maternal behaviors. • Arginine vasopressin (AVP), also known as vasopressin, argipressin or antidiuretic hormone (ADH), is a hormone found in most mammals, including humans. Vasopressin is alsononapeptide hormone. It is derived from a preprohormone precursor that is synthesized in the hypothalamus and stored in vesicles at the posterior pituitary. Most of it is stored in the posterior pituitary to be released into the blood stream; however, some of it is also released directly into the brain

44. Гормоны нейрогипофиза • arginine vasopressin - (vasopressin, AVP) A hypothalamus neuropeptide hormone stored in the posterior pituitary (neurohypophysis). The hormones actions include: stimulate liver glycogenolysis, contraction of vascular smooth muscle cells and kidney mesangial cells, antidiuresis in the kidney, and aggregation of platelets. Also in mouse, this hormone has been shown to promote maternal behavior