INTERAKSI SELULER DAN ORGANOGENESIS Ita DJUWITA

Sub Pokok Bahasan: Pengertian organogenesis Proses & mekanisme pembentukan organ Interaksi dan diferensiasi seluler Ekspresi gen & pengaruh lingkungan Fenotipe, fenokopi, pleiotropism dan letal Malformasi kongenital dan faktor-faktor penyebabnya IDW

Ketiga proses berjalan secara overlapping PERKEMBANGAN MAHLUK HIDUP (DEVELOPMENT) Proses secara keseluruhan meng perubahan embrio menjadi fetus – lahir, yg melibatkan a. Pertumbuhan/ Growth (Pembelahan sel) b. Pergerakan & Migrasi Sel (Cell Movement) c. Diferensiasi sel (Cell Differentiation) Ketiga proses berjalan secara overlapping pada saat bersamaan IDW

Proses Perkembangan mahluk hidup IDW

Terjadi penambahan jumlah sel (bahan inti dan sitoplasma) a. Pertumbuhan, Terjadi penambahan jumlah sel (bahan inti dan sitoplasma) b. Pergerakan sel, Didalam tubuh, jaringan & organ menempati lokasi yg spesifik. Utk mencapai lokasi tsb sel-sel embrio harus bergerak; migrasi dgn cara yg terprogram. c. Diferensiasi sel, Setelah menempati posisi baru, sel akan berdiferensiasi menjadi sel, jaringan atau organ utk menjalankan fungsi ttt berdasark lokasi didalam tubuh IDW

I. PENGERTIAN ORGANOGENESIS – MORFOGENESIS Morfogenesis  Perubahan bentuk eksternal Organogenesis  Perkembangan organ-organ (the making of organs) The formation of the products of the neural tube, neural crest cells, the somites, and all of the rest of the cells which develop from the three germinal layers IDW

Organogenesis is the especially initial formation of organs starting with less differentiated tissues found in the early embryo. Websters: "The origin and development of bodily organs." IDW

Websters: "The origin and development of bodily organs." Pattern & Calson, 1974

ORGANOGENESIS / MORFOGENESIS II. PROSES & MEKANISME ORGANOGENESIS / MORFOGENESIS 1. Apa yang menginisiasi terjadinya proses organogenesis/ morfogenesis ? 2. Bagaimana proses dan mekanisme organogenesis/ morfogenesis ? IDW

1. INISIASI proses organogenesis Pd Gastrulasi terjadi  perubahan bentuk & pergerakan sel-sel 3 lapis daun kecambah (primary germinal layers) (ektoderm, endoderm, mesoderm, archenteron/ gastrosul) menurunkan jaringan & organ-organ Gastrulasi  inisiasi morfogenesis & organogenesis. IDW

Ke-3 daun kecambah akan menurunkan Empat (4) jaringan utama : jaringan saraf jaringan otot jaringan penghubung jaringan epitelial There is no one-to-one correspondence between germinal layer origin and primary tissue type. IDW

Endoderm  utamanya, jaringan epitelial. The endoderm secara spesifik menurunkan: saluran digesti paru-paru liver vesika urinaria germ cells IDW

Endoderm IDW

Mesoderm  jar otot dan penghubung, jaringan epitelial The mesoderm secara spesifik menurunkan, skeleton otot-otot skeletal tulang kepala dan rahang mesoderm  somit-somit  segmentasi tubuh which divide bodies into cross sections which may be stacked, for example, from head to toe. In vertebrates the somites are originally found adjacent to the notochord and then give rise to such things as ribs and skeletal muscles. IDW

Earlier in development the mesoderm also gives rise to the epidermis, neural tube, and neural crest, from which these later structures develop IDW

2. MEKANISME proses perkembangan termasuk organogenesis Bagaimana embrio 1 sel (Zigot) dapat berkembang menjadi ORGANISME MULTISELULER? a. Pertumbuhan/ Growth (Pembelahan sel) b. Pergerakan & Migrasi Sel (Cell Movement) c. Diferensiasi sel (Cell Differentiation) IDW

b. Migrasi sel: menuju tempat yg spesifik PETA TAKDIR  right place right time POSISI SEL Cell migration The movement of cells which were born in one place to a different place in the embryo or fetus. The addition of new cells of the same type to existing sites. IDW

PETA TAKDIR  Masing sel memiliki takdir sendiri di tempat akhir TOTIPOTENSI CELL POSITION  Migrasi / gerakan Di lokasi akhir akan terjadi induksi dan diferensiasi  Jaringan dan organ-organ tertentu Utk mengemban fungsi tertentu UNIPOTENSI IDW

(Body pattern formation) Posisi sel Pada hewan, pergerakan sel / sekelompok sel sangat penting utk mentransformasi embrio kedalam bentuk 3 dimensi  Basic body plan Sumbu tubuh: Kepala - ekor; kiri - kanan; depan - belakang (Body pattern formation) Perkembangan jaringan & organ  tersusun pada tempat yg spesifik. IDW

IDW

Posisi sel mempengaruhi peta takdir & derivatnya Induksi: mempengaruhi terjadinya diferensiasi e.g., posisi notokorda  induksi ektoderm disebelahnya  membentuk lempeng saraf IDW

Contoh: Notokorda Ektoderm Buluh saraf IDW

Programmed cell death / apoptosis : The removal of cells from existing sites. Note that very often structures are produced within larger cellular structures, and completion of the structure requires some means of removal of the excess cells. For example, the development of fingers involves the removal of the tissue (webs) initially found between the forming digits. A variation on right place-right time. Chemical concentration gradients help determine relative position. IDW

c. Inisiasi Diferensiasi, diatur oleh Molekul (mRNA) dr maternal dalam sitoplasma sel embrio akan memicu proses transkripsi dr genom embrio Sitoplasma sel telur mengandung mRNA, protein & bahan-bahan lainnya yg berasal dr maternal  berpengaruh thdp awal perkembangan embrio Signal yg dikode oleh genom dari sel embrio lainnya akan menginduksi target sel IDW

Differentiation very often is irreversible. The changing of the protein expression pattern of cells in the course of their individual development and division. Differentiation very often is irreversible. That is, embryonic cells typically may become more specialized, but similarly typically more specialized (differentiated) cells are not well equipped to become less specialized. Diferensiasi terjadi pd tingkat molekuler krn adanya ekspresi gen utk menghasilkan protein tertentu; misalnya: sel otot  aktin & miosin IDW

- difusi molekul signal dan - interaksi permukaan sel Lingkungan di sekitar sel mengandung informasi (signal) berupa molekul kimiawi yg dikode oleh gen embrio  molekul dikirim ke sel target sehingga mengakibatkan perubahan pd sel target  proses induksi Induksi terjadi : - difusi molekul signal dan - interaksi permukaan sel IDW

III. INTERAKSI dan DIFERENSIASI SEL Interaksi dan induki diferensiasi sel terjadi, melalui: Difusi substansi: bekerja intraseluler Hormon, growth factor, morfogen 2. Interaksi permukaan sel IDW

IDW

Struktur membran sel, mengandung : 1. mol adesi sel 2. mol adesi substrat 3. mol junctional sel 4. mol reseptor Permukaan membran sel berubah sejalan waktu dan tempat IDW

Contoh model diferensiasi IDW

IDW

IV. EKSPRESI GEN DAN PENGARUH LINGKUNGAN Diferensiasi dikontrol oleh program genetik & dapat dimodifikasi oleh faktor lingkungan Setiap sel memiliki komplemen penuh, DNA  Dalam organisme, sel-sel yg berbeda memiliki DNA yg sama. Gen tertentu dalam beberapa sel harus ON dan pada sel lain OFF. IDW

Bagaimana Gen tertentu dalam beberapa sel harus ON dan pada sel lain OFF Dua faktor utama sel yang mengatur aktivasi gen pada proses perkembangan 1. Bahan Inti / NUCLEUS 2. Bahan SITOPLASMA

CELL NUCLEUS CHROMOSOME GENOME/ GENES/ DNA

Pengaturan Ekspresi Gen

Sel somatis pd mamalia memiliki 2 copy genome (diploid) Kontribusi nyata yg diberikan induk jantan & betina pada anak-anaknya  berbeda-beda Bagaimana gen yang diwariskan dr maternal & paternal berbeda ekspresi ? Terjadi switch off (silencing) pd salah satu copy gen induk Genomic Imprinting

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Genomic Imprinting, suatu proses EPIGENETIK yg dinamis, yg terlibat dalam pengaturan ekspresi sebagian kecil gen dari genome mamalia melalui proses modifikasi STRUKTUR DNA Memberikan efek terhadap fenotip Pd setiap generasi harus mampu di HAPUS (Off) dan BENTUK (On)

Epigenetic reprogramming in germ cells is critical for imprinting, and reprogramming in early embryos also affects imprinting. In germline cells the imprint is erased, and then re-established according to the sex of the individual; i.e. in the developing sperm, a paternal imprint is established, whereas in developing oocytes, a maternal imprint is established. The process of erase and reprogramming is necessary such that the current imprinting status is relevant to the sex of the individual.

Ada 2 mekanisme utama yg terlibat dalam terjadinya imprinting, yakni: 1. Modifikasi Asetilasi Histone 2. Modifikasi Metilasi DNA

1. Asetilasi HISTONE (Aktif transkripsi)

Asetilasi residu lisine pd posisi terminus dr protein histone menghilangkan muatan positif  mengurangi afinitas protein histon ke DNA Enzim polimerase RNA polymerase dan faktor transkripsi lebih mudah berikatan pada promoter Umumnya, asetilasi histon memicu transkripsi; deasetilasi histon menekan transkripsi

Acetylation (or ethanoylation): reaction that introduces an acetyl functional group into an organic compound. Deacetylation is the removal of the acetyl group. Introducing an acetyl group into a compound, the substitution of an acetyl group for an active hydrogen atom. A reaction involving the replacement of the hydrogen atom of a hydroxyl group with an acetyl group (CH3 CO) yields a specific ester, the acetate. Acetic anhydride is commonly used as an acetylating agent reacting with free hydroxyl groups.

Acetylation of proteins In biology, i.e. in living cells, acetylation occurs as a post-translational modification of proteins, for example, histones and tubulins. Histone Acetylation and Deacetylation In histone acetylation and deacetylation, the histones are acetylated and deacetylated on lysine residues in the N-terminal tail as part of gene regulation. Typically, these reactions are catalyzed by enzymes with "histone acetyltransferase" (HAt) or "histone deacetylase" (HDAc OR HDs) activity.

Several different forms of HATs and HDs have been identified.  Among them, CBP/p300 is probably the most important, since it can interact with numerous transcription regulators.

2. Modifikasi Metilasi DNA Pd embrio preimplantasi terjadi perubahan mayor melalui mekanisme imprinting yakni metilasi DNA Perubahan metilasi DNA diwariskan secara stabil melalui pembelahan sel shg akan tetap sampai tahap fetus.

Penambahan CH3 pada cytosine  Silencing Gene Expression METILASI DNA deaminasi metilasi Penambahan CH3 pada cytosine  Silencing Gene Expression Metilasi residu cytosine  5-methylcytosine Deaminasi 5-methylcytosine  thymine.

Pola Metilasi DNA di-program kembali (reprogramming) pada 2 periode perkembangan, yakni: - pada germ cells - pad embrio preimplantation Jika terjadi kerusakan/ gangguan dalam proses atau pemeliharaan imprinting pd masa perkembangan embrio preimplantasi (kultur atau manipulasi embrio), dapat mengakibatkan: - Fetal Loss atau - Large Offspring Syndrome.

Methylation is a process that is used to control gene expression, and it is what determines the timing of gene expression  (as in embryologic development, in which genes are turned on and off in a sequential fashion), inactivation of an X-chromosome in a female ("Lyonization"), and, in mammals, differential expression of certain genes depending upon whether they are maternally- or paternally-derived ("genomic imprinting").

DNA METHYLATION After replication, daughter strands of fully methylated DNA are hemimethylated (reaction 3) and the original pattern of DNA methylation is maintained by the DNA methyltransferase (reaction 2), which preferentially methylates the cytosine residues at hemimethylated CpG sites. Further replication without methylation of the hemimethylated DNA results in fully unmethylated DNA (reaction 4). De novo methylation (reaction 1) is also considered to be mediated by the DNA methyltransferase, although the efficiency of de novo methylation is low. (Goto and Monk, 1998)

Regulation The grouping of imprinted genes within clusters allows them to share common regulatory elements, such as non-coding RNAs and differentially methylated regions (DMRs). When these regulatory elements control the imprinting of several genes in a given region, they are known as imprinting control regions (ICR). The expression of non-coding RNAs, such as Air on mouse chromosome 17 and KCNQ1OT1 on human chromosome 11p15.5, have been shown to be essential for the imprinting of genes in their corresponding regions.

V. FENOTIPE, FENOKOPI, PLEIOTROPISM GEN: Fragmen DNA yg mengkode suatu polipeptida LOKUS : Lokasi gen pada kromosom   Kepentingan Lokus: Terapi gen & Rekayasa gen Perbedaan antara linked & Unlinked Gene: Linked gen: terletak pada kromosom yg sama; Unllinked gen: terletak pada kromosom yang berbeda. IDW

Hubungan antara GEN, ALLEL, & TRAITS (karakter)   GEN mempresentasikan traits ALLELES = GENOTYPE   PHENOTYPE T,t                  Tinggi tanaman        T=tinggi / t=pendek Interaksi ALEL akan menentukan karakter Pada @ GEN, Individu diploid memiliki maks 2 Alel   Jk kedua alel sama  organisme disebut HOMOZYGOUS  Jk kedua alel beda  HEROZYGOUS. IDW

FENOKOPI  keadaan fenotipe yg dipengaruhi oleh faktor eksternal PLEIOTROPISM  gen tunggal yg memiliki multi efek IDW

VI. MALFORMASI KONGENITAL dan FAKTOR-FAKTOR PENYEBAB PENGERTIAN MALFORMASI KONGENITAL PERIODE KRITIS DARI PERKEMBANGAN TERATOLOGI FAKTOR PENYEBAB MALFORMASI IDW

PENGERTIAN MALFORMASI KONGENITAL Katogori luas  "Congenital disorders"  meliputi berbagai kondisi: Minor physical anomalies (e.g., a birthmark), Severe malformations of single systems (e.g., congenital heart disease or dysmelia), Kombinations of abnormalities affecting several parts of the body. Congenital defects of metabolism Ada 3 tipe utama congenital disorders: Congenital physical anomalies inborn errors of metabolism Other genetic disorders IDW

PENGERTIAN MALFORMASI KONGENITAL Congenital physical anomaly  abnormalitas struktur dari suatu bagian tubuh. Anomali  menjdi atau tidak menjadi masalah Umumnya orang memiliki 1 atau lebih anomali fisik IDW

- Anomali minor  kurvatura pd jari kelima (clinodactyly) Contoh anomali fisik: - Anomali minor  kurvatura pd jari kelima (clinodactyly) - preauricular pits), - Pemendekan tulang metacarpal / metatarsal ke-4 - dimples over the lower spine (sac dimples). Bbrp anomali minor  indikasi adanya internal anomali yg signifikan IDW

Malformasi kongenital  jk anomali fisik bersifat hebat  cacat struktur  masalah malformation syndrome.  Kombinasi malformasi  mempengarhi > 1 bagian tubuh Birth defect (Cacat lahir)  istilah umum utk congenital malformation, i.e. anomali fisik yg dikenali sehak lahir & secara nyata merupakan masalah IDW

Genetic disorder / diseases Semua mrpk kongenital, walaupun tidak tampak / terekspresi Genetic diseases, dibagi dalam : Single-gene defects, multiple-gene disorders, atau chromosomal defects. Single-gene defects: akibat abnormalitas gen autosomal (2 kopi/ recessive disorder) atau (1 kopi/ dominant disorder). Bbrp akibat delesi atau abnormalitas beberapa gen pada 1 kromosom IDW

Mempengaruhi bbrp bagian tubuh yg berbeda atau sistem organ Chromosomal disorders: hilangnya atau duplikasi sebagian besar kromosom (ratusan gen) atau kromosom intak (utuh) Mempengaruhi bbrp bagian tubuh yg berbeda atau sistem organ Congenital metabolic disease: disebut inborn error of metabolism. Umumnya defek gen tunggal (diturunkan)  mempengaruhi struktur atau fungsi bagian tubuh IDW

Congenital disorder  kondisi medis yg tampak saat lahir. Namun sebenarnya dapat dikenali sejak prenatal, saat lahir atau saat dewasa atau tidak sama sekali Congenital disorders Dapat diakibatkan oleh: Abnormalitas genetik Kondisi lingkungan intrauterine Errors pd morphogenesis, atau Unknown factors. Congenital conditions Dapat merupakan suatu: Penyakit, defek, disorders, anomalies, atau perbedaan/variasi genetik IDW

Teratology (from the Greek τέρᾰς (genitive τέρᾰτος), monster, atau marvel and λόγος, Abad ke17  sesuatu yg tampak aneh/ abnormal Abad ke19 berkaitan dgn biological deformities medical study  teratogenesis, congenital malformations atau individu dgn kelainan bentuk makroskopis. Dysmorphology  the study of abnormal form . IDW

PERIODE KRITIS PERKEMBANGAN IDW

FAKTOR-FAKTOR PENYEBAB MALFORMASI KONGENITAL 1. Endogenous 2. Exogenous 3. Multifactorial Inheritance IDW

Defek CNS Berdasarkan Waktu Terjadinya A. Neurulation Defects 1. Primary a. anencephaly b. meningoencephalocele c. mylomeningocele 2. Secondary a. diastematomyelia b. tethered cord 3. Spina Bifida a. spina bifida occulta b. spina bifida cystica IDW

1. Lissencephaly (agyria) 2. Pachygyria 3. Polymicrogyria B. Migration Defects 1. Lissencephaly (agyria) 2. Pachygyria 3. Polymicrogyria 4. Cortical heterotropia 5. Schizencephaly IDW

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