Sex Differentiation The goal of these lectures is to discuss how a control system is formed. For this, we will use basic physiology associated with the control of reproduction (from sexual differentiation to adult reproductive function), as an example. The sections for this lecture are: 20 Introduction Sexual differentiation Development of a control system Overview, male/female reproduction How a circle is formed Life is a series of chemical reactions occurring in compartmentalized environments. The main purpose of life is to keep itself alive Physiology, the study of how life works, is based on the simultaneous occurrence of the following three concepts: levels of organization structure / function relationship homeostatic regulation Course Outline Topic # Topic lecture Silverthorn Week 1 to week 2 Topic #1 Topic #2 Introduction (pre-requisite material) Membranes (pre-requisite material) 1-5 1-5 Pre-requisite Material (chapter # 5) Topic #3 Homeostasis and Signal Transduction 6 lectures, Topic #4 Endocrine Communication and the Endocrine System 7 recitations, Topic #5 Neural Communication and the Sensory System 8-11 office hours, review, Topic #6 Muscle, Muscle Contraction and their Regulation 12-13 exam1 (chapter # 8) REVIEW #1 material from topic #01 #06 EXAM #1 material from topic #01 #06 (33%) 1-13 1-13 Week 3 to week 4 Topic #7 Topic #8 Basic Physiology of the Cardiovascular System Basic Physiology of the Respiratory System 14-17 18 lectures, recitations, review, exam2 Topic #9 Basic Physiology of the Renal System 19-20 (chapter # 7) REVIEW #2 material from topic #01 #09 EXAM #2 material from topic #01 #09 (33%) 1-20 1-20 Week 5 to week 6 Topic #10 Topic #11 Basic Physiology of the Gastrointestinal System Food Intake, Metabolism, Energy Balance and Exercise 21 23-25 lectures, recitations, review, exam3 Topic #12 From Sexual Differentiation to Adult Reproduction 26 (chapter # 6) REVIEW #3 material from topic #01 #12 EXAM #3 material from topic #01 #12 (33%) 1-26 1-26 (all tests are cumulative) 1
Introduction ( important question ) male? female Introduction ( important question ) 2
Sexual differentiation events in sexual differentiation (develoment of chromosomal, gonadal, and phenotypic sex) genetic sex established at conception governs development of gonadal sex, and this in turn regulates development of phenotypic sex in undifferentiated gonad cortex --> ovary and medulla --> testis endocrine control phenotypic differentiation, role of testicular hormones in male development female pattern is default unless testis-determining factor (TDF), a transduction factor of SRY gene (sexdetermining region of Y gene), is present disorders of sex differentiation (chromosomal sex, gonadal sex, phenotypic sex) hypothalamic differentiation, sexual dimorphic areas and the androgenized female model olfactory placode as apparent origin of GnRH neuron system and its migration to the ME development / maturation of female HPG axis as intro to puberty and to adult cyclicity external features external genitalia egg 2 sex char. sperm genetic sex gonadal sex phenotypic sex internal urogenital system FSH-LH secretion CNS sex beh. Sexual differentiation TDF of SRY gene as master switch for downstream differentiation genes embryo without Y develops as female embryo with multiple X + 1Y = male XX injected with SRY gene ---> male SRY turns indifferent genital ridge into medullary development of testis, tes-tosterone production, male phenotype SRY gene is normally present in males but its locus was deduced from XX in-dividuals with testis development that inherited 40kb Y chrosmosome (n=4) gain of function mutations in genes downstream might explain testis in XX Y X XY SRY product testost. testis male X XX X ovary female phenotype?? 3
Sexual differentiation Sexual differentiation q steroid hormone receptors function as liganddependent transcription factors by binding to unique response elements in promoter of specific target genes q orphan receptors, which have been cloned by homology, have no known ligands but appear to be mediators of adult endocrine function and organogenesis q SF-1 = Ad4BP is one of these receptors. It closely resembles the Drosophila Ftz-F1, which regulates the developmental homobox gene fushi tarazu (for paired body components) q SF-1 transcripts are found in steroid-producing organs, in Sertoli cells, in pituitary gonadotrope, and in the VMN q during formation of bipotential gonad, sexual differentiation (sexually dimorphic pattern), and in the adult gonad q expressed in developing gonadotropes prior to expression of alpha and ß subunits of LH & FSH, but not in LHRH neurons q SF-1 knockout mice die of corticoid insufficiency (volume depletion, low corticosterone, high ACTH), have female external & internal genitalia regardless of chromosomal sex, do not express LH & FSH, and do not have the VMN a proposed homeostatic relay center involved in metabolic and reproductive control 4
Sexual differentiation embryonic differentiation of internal genitalia gonocytes from yolk sac move to gut and seed undifferentiated gonad: male / medulla, female / cortex gonadal anlagen is visible at 4 weeks gestation, testis at 7 & ovary at 13-16 weeks in females apoptosis of Wolffian system in males anti-mullerian hormone (AMH), a member of the TGFß family of peptides yolk sac maternal blood supply embryo future umbilical cord Sexual differentiation testosterone, prohormone for DHT and E2 female genitalia in the absence of Y male genitalia is dependent of androgen production by the testis. Timing, effect of congenital adrenal hyperplasia in XX testosterone, critical period, hypothalamic sexual diferentiation and reproductive cycles T 5α reductase DHT nucleus differentiation of male external genitalia (development of penis & scrotum) TESTOSTERONE T nucleus differentiation of male internal genital ducts & adult 2nd sex characteristics T aromatase E2 nucleus differentiation of a male hypothalamus (tonic vs phasic control of LH) 5
Sexual differentiation Sexual differentiation Humans 6
Sexual differentiation Sexual differentiation 7
Control ( the circle ) basic theoretical mechanism for reproductive cyclicity (neonatal androgenization, POA-ES) potential areas for steroid positive feedback on the GnRH surge (E2 vs electrical stimulation in androgenized rats) NET cells, inputs and outputs to portal vessels (expt: pituitary deafferentation, transplant, HHA, ME, glia and portal vessels) maturation of black boxes & links of HPG axis (from gonad to hypothalamic function) 1500 GnRH neurons in each species accross phylogenetic scale (GnRH neuroanatomy, chem structures, POA to hypogonadal mouse) modification of GnRH as agonist / antagonist (GnRH degradation, superagonist as reproduction tool, ideal contraceptives) GnRH, sex and territorial behavior (lordosis and midcentral gray, hypocampus and GnRH, Haplochromis burtoni and territorial warfare) GT-1 cells (neuroanatomy, introduction to basic in vitro release and biosynthesis studies) linking black boxes or the maturation of the HPG axis decreasing inhibitory tone, such as opioids and Gaba increasing excitatory inputs, such as those mediated by NE, NPY, EAA, and glial TGFα synchronization of excitatory inputs with circadian oscillator amplification of diurnal pattern of GnRH release, leading to an increased afternoon release of LH preovulatory surge of GnRH & LH Control ( the circle ) Examples of maturational events in the HPG axis LHRH migration from olfactory placode pulsatility intrinsic role of LHRH neuron LHRH differentiate AP - gonadotrophs fetal FSH / LH receptor uncoupled to AC early neurogenic link from AHA- POA to the ovary lack fetal E2 - Fb helps early growth of primordial follicles stimulatory E2 on LH surge occurs years after birth prepubertal Prl / GH rises FSH ability to induce LH receptor stimulatory VIP (E2,P4), adrenergic nerves & Epi acting by ß-receptors (P4) are established in prepubertal period Lesion 1 8
Reproduction ( the HPG axis ) Male Reproduction 9
Female Reproduction this topic will be covered next lecture as an integration example Female Reproduction 10
Female Reproduction Female Reproduction 11
Female Reproduction 12