MSPC 235 Development of the Limbs PDF

DEVELOPMENT OF LIMBS MSPC 235 BY FREDERICK KWAKU ADDAI, PHD, FWACM DEPARTMENT OF ANATOMY, SMD KNUST, KUMASI  “The greatest weapon against stress is our ability to choose one POSITIVE thought over anot...

DEVELOPMENT OF LIMBS MSPC 235 BY FREDERICK KWAKU ADDAI, PHD, FWACM DEPARTMENT OF ANATOMY, SMD KNUST, KUMASI  “The greatest weapon against stress is our ability to choose one POSITIVE thought over another.” THOUGHT -William James (American Philosopher). “Father of American Psychology” 1842-1910 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 2 PRE-REQUISITE KNOWLEDGE (P-RK) Gastrulation Craniocaudal folding (head fold, tail fold), and lateral fold of embryo Signal transduction (the process by which cells communicate and affect each other’s behaviour) Growth determining factors (GDFs) –the molecules which instruct embryonic cells to multiply, move, differentiate, or die (by apoptosis) 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 3  P-RK –Embryonic folding from Week 4 Flat trilaminar embryonic disc folds along longitudinal and transverse axes (or respectively, median and horizontal planes) Consequently, embryo becomes cylindric and has a body wall Folding results from rapid embryonic growth, especially of the neural tube Foldings occur simultaneously and are not separate sequential events 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 4  P-RK – Signal Transduction Pathway of Signaling a series of chemical reactions in which a group of molecules in a cell work together to control a cell function, such as cell division, cell death, cell migration, or cell differentiation 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 5 P-RK : Molecular Signal Transduction in Embryonic Development - GDFs 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 6  GDFs in Epithelial-Mesenchymal interactions Limb bud development results from a series of epithelial- mesenchymal interactions between the mesenchymal cells of the lateral plate mesoderm and the overlying ectodermal cells 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 7 Student Learning Outcomes(1) At the end of this lecture, you should be able to do the following. 1. Understand epithelial-mesenchymal interactions in limb development 2. Explain how the limb bud forms from lateral plate mesoderm 3. Identify the genes that specify the position and outgrowth of limb buds 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 8  Student Learning Outcomes(2) At the end of this lecture, you should be able to do the following. 4. Give location/role of AER, ZPA, and Progress zone in limb bud 5. Give changes/features of limb bud at weeks 4, 6, 7, 8 and 12 6. Compare developmental similarities/dissimilarities between upper and lower limb buds 7. Give terminologies for anomalies of limb development given in the lecture 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 9 Somatic lateral plate mesoderm Recall that mesoderm differentiates into 3 regions From medial to lateral on either side of the notochord Lateral plate mesoderm is split by development within it, of the intraembryonic coelom Superior leaflet of lateral mesoderm related to ectoderm is somatic or parietal mesoderm 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 10 Limb development Appear as limb buds in 4th wk. Outpocketings from ventrolateral body wall Core of somatic lateral plate mesoderm activates limb bud formation Ectoderm at distal border thickens to form apical ectodermal ridge (AER). 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 11  The Limb bud First appear on Three regions of each the ventrolateral limb bud are notable body wall initially and extend 1. Apical ectodermal ridge ventrally. (AER) 2. Zone of polarizing activity (ZPA) 3. Zone of proliferation 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 12 Apical Ectodermal Ridge (AER) AER is one of the main signalling centres during limb development It controls outgrowth and patterning in the proximo- distal axis 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 13 Zone of Polarizing Activity (ZPA) A group of cells located in the posterior mesenchyme of the limb bud Contains signals which instruct the developing limb bud to form along the anterior/posterior axis Thus, ZPA acts as the organizer of the A-P polarity of the limb bud 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 14 Zone of Proliferation Also known as the Progress zone Progress zone A layer of mesodermal cells immediately beneath the AER in the developing limb bud The fate of the mesodermal cells is patterned by the length of time spent in the progress zone during limb outgrowth 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 15 Limb development - Hand & Foot plates Upper limb buds appear first followed by lower limb buds 2-3 days later By 6th week limb buds are flattened –and known as hand and foot plates 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 16 Limb development - Hand & Foot plates Circular constrictions indicate wrist and axillary boundaries 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 17 Formation of digits Fingers and toes form when programmed cell death (apoptosis) in the AER separates the ridge into five parts 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 18  Limb development By week 8 limbs have fully formed After 8th week they grow in size relative to the body As limbs grow cells near the flank respond to retinoic acid (as GDF) and differentiate into the stylopod (humerus/femur) Last to differentiate is the Next to differentiate is the autopod (wrist & fingers, and zeugopod (radius/ulna and tibia/fibula) ankle and toes 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 19 Skeleton of limbs Mesenchyme forms hyaline cartilage models of bones. 12th wk –ossification centres appear Endochondral bone formation replaces cartilage model with osseous tissue in Mouse limb skeleton development limbs 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 20 Molecular aspects – Limb Development Molecular regulation- Positioning along craniocaudal axis regulated by homeobox genes (HOX genes). Limb outgrowth – initiated by T-Box genes TBX5 and FGF10 in forelimb TBX4 and FGF10 in hindlimb 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 21 Molecular aspects TBX4, TBX5, FGF 10 secreted by lateral plate mesoderm. Bone morphogenetic proteins (BMPs) from ventral ectoderm, induce AER. Cells of AER express FGF4 and FGF 8 which maintain progress zone for limb growth. Other molecules include SHH, WNT7a 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 22 Segmental position of Limbs Upper limb buds lie adjacent to lower 5 cervical and upper 2 thoracic spinal segments Lower limb buds lie adjacent to the lower four lumbar and upper three sacral spinal segments 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 23 Limb rotation – week 7 Upper limb buds rotate 900 laterally Hence extensor muscles lie lateral and posterior, and thumbs lie laterally Lower limbs rotate 900 medially Hence extensor muscles are anterior, and the big toes are medial 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 24  Rotation and elongation Diagram showing lateral rotation of upper limb Diagrams showing orientation of limbs buds, and medial rotation of the lower limb buds. before(wk. 6) and after (wk. 8) rotation 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 25 Limb axis determination 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 26 Upper vs lower limb shape formation CHANGES FROM THE 4TH TO THE 9TH WEEK Note that shape of limb is completely formed by 8th week UPPER LIMB BUD LOWER LIMB BUD 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 27  Anomalies of limb development -thalidomide Thalidomide was tranquilizer that was also used to stop morning sickness in pregnancy Over 80% of children born to mothers who took thalidomide had limb defects Defects ranged from absence of limbs (amelia), or proximal limb components (phocomelia), to loss of thumb or digit tip Drug inhibited development of new blood vessels in developing limbs 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 28 General classification of limb anomalies 1. failure of formation of parts, 4. undergrowth, failure of differentiation 5. congenital constriction band (separation) of parts, syndrome 2. duplication, 6. generalized skeletal 3. overgrowth, abnormalities 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 29 Anomalies Polydactyly 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 30 Anomalies 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 31 Anomalies of limb formation Shortened digits – brachydactyly Absence – Amelia Partial absence – Meromelia Polydactyly – extra digits - Ectrodactyly – absence of a digit - unilateral Syndactyly – fused digits 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 32 summary 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 33 The End HAVE A GOOD DAY! 25/10/2024 fka/UGMS-MSPC 235/CLASS OF 2029 34