05.22.09: Musculoskeletal

Author(s): Deneen Wellik, Ph.D., 2009

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Musculoskeletal

Deneen Wellik M1 Embryology Spring 2009Day 34 - Human Embryo

Reading: Langman’s Medical Embryology, Chapters 9, 10

Carlson: Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.

Gastrulation produces the three germ layers:endoderm, ectoderm and mesoderm

HN

PS

Som

PS

PSM

Most visible result of gastrulation - somites!

Source Undetermined

Tissue sources from which the musculoskeletal system derives(almost all mesodermal):

1. most of the axial vertebrae,cranial vault, base of skull

2. limb skeleton, sternum of axial skeleton scapula, pelvis

3. bones of the face (neural crest)

SKELETON:

Gilbert. Developmental Biology, Sinauer and Associates. Eighth Edition

Tissue sources from which the musculoskeletal system derives(almost all mesodermal):

1. skeletal muscle (limbs and trunk),voluntary facial muscle

2. smooth muscle cardiac muscle

MUSCLES:


Somites

-Indistinguishable blocks of mesoderm adjacent to either side of the neural tube


intermediate mesoderm

Somites give rise to: vertebra and ribs dermis skeletal muscles of back,

body wall and limbs

(important for migration of neural crest and spinal nerves)

lateral plate mesoderm


BMP

noggin

BMP/noggin: early, critical signal for mesodermal differentiation

Noggin-secreting cells ectopically placed in lateral plate mesoderm respecify that mesoderm into somite-forming paraxial mesoderm

Gilbert. Developmental Biology, Sinauer and Associates. Eighth Edition (Both images)

Properties of somitogenesis:

1. It is a sequential and directional process: the oldest somites are located anteriorly (and are more differentiated); the youngest somites are located most posteriorly.

2. It is a periodic process; new boundaries form after a given amount of time.

3. The vertebrate body shows bilateral symmetry.

4. Somite boundary formation is synchronous.


As somitogenesis is a continuous process, various stages of somitogenesis are present simultaneously in the developing embryo.

Source Undetermined

Overview of somitogenesis/segmentation process:

Source Undetermined

Raldh2

Fgf8

Molecular model of somitogenesis:

Source Undetermined

Cycling of Notch Pathway in PSM (pre-somitic mesoderm)


Disruptions in the Notch pathway result in segmentation defects (irregular and fused elements)

Dll3


Each somite differentiates into sclerotome, dermatome and myotome;Sclerotome forms the axial skeleton.

Source Undetermined

Source Undetermined

Progression of development after somite formation: Specification and more changes in epithelialization.


Hoxa11Sox9

A molecular snapshot of differentiation along the AP axis:

D. Wellik

Resegmentation: Cells from the caudal half of one somite and cells from the cranial half of the adjacent caudal somite form one vertebral body.

Source Undetermined

Patterning the axial skeleton - specification of the somite along the anteroposterior (AP) axis:Although the basic cellular differentiation pattern of somites at different axial positions is very similar, unique vertebral structures form along the craniocaudal axis, indicating that somites acquire specific identities according to their axial position.


Morphological identity of axial skeleton determined at pre-somitic mesoderm stages; correlates with maintenance of Hox expression.

Hoxa5Hoxa6Hoxa7

Hoxa7Hoxa6Hoxa5

Source Undetermined

In heterotopic transplants, Hox expression is conserved

Hoxa9

Hoxa9

Source Undetermined

Paralogous Hox genes are redundant in mammalian patterning(paralog groups shown color-coded below)

ANT-C

Drosophila

BX-Clab pb Dfd Scr Antp Ubx AbdA AbdB

A1 A3 A4 A5 A6 A7 A9 A10 A11 A13 A2HoxA

B1 B3 B4 B5 B6 B7 B8 B9 B13 B2HoxB

C4 C5 C6 C8 C9 C10 C11 C12 C13HoxC

D1 D3 D4 D8 D9 D10 D11 D12 D13HoxD

Mouse/Human

Evx1

Evx2

D. Wellik

C

ontr

ol

T12 L3 S2 C5

*** *

Sacral

}Lumbar

{T13

T13

T13

}

{

*** *

*** *

}

{

T12 L3 S2 C5

T12 L3 S2 C5

1

0aac

cdd

11aa

ccdd

‘Segment transformation’Sacral --> Lumbar

‘Segment transformation’Lumbar --> Thoracic

Loss of paralogous function results in

complete loss of regional identity in axial column

Wellik and Capecchi, Science, 2003

Ribs and Sternum:

Unlike the rest of the axial skeleton (vertebrae and vertebral ribs, the sternum derives from lateral plate mesoderm

intermediate mesoderm

lateral plate mesoderm

somites/paraxial

mesoderm


Two sternal bands condense bilaterally in the lateral plate mesoderm in the ventral body wall, migrate around the developing embryo and fuse at the midline to become the manubrium, sternebrae and xiphoid process


Things that can go wrong : Result:

1. Disruption of growth of PSM (Fgf8) No vertebrae

2. Disruption of patterning of PSM (Notch) Irregular/fused

vertebrae

3. Incomplete closure of vertebral bodies spina bifida

4. Disruption of specification pathway (Hox) Changes in

vertebral identity

(morphology)

Many developmental abnormalities occur in the axial skeleton

5. Failure of lateral plate midline fusion split sternum

blue: neural crestred: somites/somitomeresyellow: lateral plate mesoderm

The skull,made of two parts:

1. Neurocranium: the protective case around the brain- derived from neural crest and paraxial mesoderm (characterized by spicules)

2. Viscerocranium: the facial skeleton- derived from neural crest

Sadler. Langman’s Medical Embryology. Lippincott 2004. 9th ed.


Newborn Skull:

At birth, flat bones are separated by sutures and fontanelles; allows molding at birth.

Cranial capacity increases very little after 5-7 years of age.

Some sutures remain open until adulthood.

Palpitation of anterior fontanelleprovides valuable information onproper ossification ofthe skull.


Craniofacial Defects:

Cranioschisis: abnormal cranial vault formation due to failure of cranial neuropore closure

anencephaly

meningocele




Craniosynostosis: premature closure of one or more sutures (1:2500 births and more than 100 syndromes)

Scaphocephaly:early closure of

sagittal suture

Brachycephaly:early closure of

coronal/lambdoidal sutures



Thanatophoric dwarfism: Dwarfism with or without cloverleaf skull (abnormal growth of skull base with premature closures of all cranial sutures); neonatal lethal; autosomal dominant.



Microcephaly: generalized failure of brain growth; results in severe mental retardation

Acromegaly: congenital hyperpituitarism which results in excessive production of growth hormone; usually disproportianal enlargement of face, hands and feet (sometimes results in symmetrical growth)

Two types of ossification:

1. Endochondral: mesenchyme differentiate into cartilagenous condensates, which then become ossified (i.e. axial, limb)

2. Intramembranous: mesenchymal cells differentiate directly into bone (i.e. flat bones of the skull).

Muscular system(Muscle is of mesodermal origin):

Skeletal muscle derives from somites

Smooth muscle derive from splanchnic lateral plate mesoderm

Cardiac muscle derives splanchnic lateral plate mesoderm of the heart tube

Voluntary facial muscles derive from anterior somitic mesoderm

Skeletal muscles form from somites (paraxial mesoderm)

Each somite differentiates into sclerotome, dermatome and myotome;Myotome forms muscles.

Sclerotome becomes axial skeleton and ribs

Myotome forms most of the body and limb musculature

Dermatome gives rise to the dermis of the skin

Source Undetermined

Source Undetermined

Stages of somite differentiation:

1. Completely epithelialized

2. Mesenchymal transformation of ventromedial somite into sclerotome

3. Myotome separates from dermo-myotome

4. Dermatome de-epithelializes to become dermal fibroblasts


By the end of the fifth week, prospective muscles are found divided into two parts:Epimere - back muscles (from dorsomedial lip of myotome)Hypomere - body wall and limb muscles (from ventro medial lip of myotome)


Mature limb has no segments, but dermomyotomal pattern can still be recognized in the adult.

5 weeks 6 weeks

7 weeks


Determination of the Myotome:- Shh and noggin, secreted by the notochord and floor plate cause the ventral part of the somite to express Pax1 to form sclerotome. - Wnts signaling (dorsal neural tube) and low Shh (notochord) activate Pax 3, which induces dermamyotome.

- Wnts also direct the dorsomedial portion of the somite to form epaxial (back) muscles. - NT-3 directs dermatome differentiation. - Hypaxial (limb and body wall) muscles are formed from dorsolateral portion of the somite due to Wnt and Bmp4 signalling. - Both muscle pathways direct MyoD and/or Myf5 signaling.


Wnt, Shh,

Myf5, MyoD

Conversion of myotome to muscles cells require multiple steps:All cells fated to become muscle, express MyoD

Developmental Biology, Sinauer and Associates. Eighth Edition

Committed myoblasts in culture divide and proliferate (without differentiating) in the presence of growth factors (primarily FGFs), but show no muscle-specific protein expression. When the growth factors are used up, the cells cease to divide, align and fuse into myotubules. When the myoblasts align

(but prior to fusion), they cease to divide (shown here by lack of incorporation of radiolabeled thymidine).

Myotubes form when myoblasts align and fuse. The cell membranes between the multinucleate, aligned cells dissolve (requires Myogenin).

If adhesion in these cells are experimentally blocked, differentiation does not proceed.


Myogenesis occurs in two phases, the first results in the formation of primary myotubes - these arise prior to innervation by motor neurons. Secondary myotubes, which are smaller, form adjacent to primary tubules, arise after motoneuron innervation and depend upon it. They are electrically coupled.

Satellite cells: Lineage is unclear, but persist after development and are capable of proliferating in response to muscle fiber damage.


Cardiac Muscle:Develops from splanchnic lateral plate mesoderm surrounding heart tube. Myoblasts adhere, but do not fuse to one another and, later in development, form intercalated discs. Later still a few specialized bundles of muscle cells, the Purkinje fibers, form the conducting system.

Smooth Muscle: Mostly derived from splanchnic lateral plate mesoderm, but part of aorta and coronary arteries are neural crest derived. Only the sphincter, the dilator muscle of the pupil, mammary and sweat gland muscles are derived from ectoderm.

Syndetome

4th Somitic Compartment

Defined by expression of scleraxis.

This population arises between myotome (after involution under dermomyotome) and sclerotome.

From sclerotomal compartment.

Gives rise to the tendons.


Places tendons in correct position in the axial skeleton…

C. Taubman

Limb scleraxis expression; in limb tendons also direct muscle attachment


Limb bones and connective tissuederive from lateral plate mesoderm

Limb Growth and Development

Source Undetermined

EARLY LIMB PATTERNING:

Limb formation initiates during the fourth week of development (E9.0 in mouse) as the primary axis (AP) is still elongating. First the forelimb and then the hindlimb begin as protrusions from the lateral plate mesoderm at the sides of the embryo. Limb buds consist of a core of mesenchyme and an outer covering of ectoderm.

1 in 200 live human births display limb defects.

Forelimb bud

Hindlimb bud

Source Undetermined

Limb skeletal elements:

Chicken Mouse

Stylopod: The proximal element of a limb that will give rise to the humerus in the forelimb and femur in the hindlimb

Zeugopod: The intermediate element of a limb that will give rise to the radius and ulna in the forelimb and the tibia

and fibula in the hindlimbAutopod: The distal elements of a limb that will give rise to the

wrist and the fingers in the forelimb and the ankle and toes in the hindlimb

Niswander. Pattern Formation: Old models out on a limb. Nature.com. February 2003, volume 4.

Proximal Distal

Posterior

Anterior

Dorsal: top of hand/pawVentral: palm

Limb axes:


Human Limb Development

5 weeks 6 weeks 8 weeksSadler. Langman’s Medical Embryology. Lippincott 2004. 9th ed.

Limbs rotate inwardDay 33: hand plate, forearm, shoulderDay 37: Carpal region, digital plateDay 38: Finger rays, necrotic zonesDay 44: toe raysDay 47: horizontal flexionDay 52: tactile pads

A-P (fingers); D-V (palm); P-D (length)

5 weeks

6 weeks

8 weeks


At 6 weeks, the terminal portion of the limb buds flatten to form hand- and footplates. Fingers and toes (digits) are formed when cell death in the AER separates the plate into five parts. Digits continue to grow and cell death in intervening mesenchymal tissue delineates the digits.

41 days 51 days

56 days

Bmp signaling


While external shape is being established, the mesenchyme begins condensing and chondrocyte differentiation ensues. The first cartilage models are formed in the sixth week of development. Joints form at regions of arrested chondrogenesis by cell death.

early 6 weeks

early 8 weeks

late 6 weeks


Endochondral bone formation:A. Mesenchyme begins to condense into chondrocytesB. Chondrocytes form a model of the prospective boneC. Blood vessels invade the center of the model, where osteoblasts localize,

and proliferation is restricted to the ends (epiphyses)D. Chondrocytes toward the shaft (diaphyses) undergo hypertrophy and

apoptosis as they mineralize the surrounding matrix.

Growth of the long bones is maintained by proliferation of chondrocytes in the growth plates (long bones have two growth plates, in smaller bones (phalanges), there is only one at the tip)

12 weeks

(after birth)


Molecular Regulation of Limb Development:Known molecular interactions coordinate limb growth and patterning along three axes:

1) Dorsal to ventral (Lmx1b, Wnt7A, BMP/En1)2) Proximal to distal (Fgf4/8)3) Anterior to posterior (Shh/Gli3)

GLI3 R/A

University of the Basque Country Press, 1990.

LIMB BUD OUTGROWTH: Fgf8 is expressed shortly after limb bud outgrowth and quickly becomes localized to the Apical Ectodermal Ridge (AER)

AER



Molecular control of dorsoventral (DV) patterning:

Early mesenchymal signals establish Wnt7a expression in the dorsal ectoderm and Lmx1 expression in the dorsal mesenchyme.- Loss of expression results in bi-ventral limbs.

Expression of Wnt7a is restricted to the dorsal ectoderm because it is repressed in the ventral ectoderm by En1. En1 expression is induced by BMP signaling.-Loss of expression results in bi-dorsal limbs.

-Important Note: Disruption of DV patterning does NOT affect specification of the skeletal elements.Carlson: Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.


Juxtaposition of Wnt7a and En1 promotes formation of the AER

1 = AER6 = dorsal (Wnt7a)5 = ventral (En1)2 = mesenchyme

Junction = AER

Source Undetermined

At the tip of the limb bud a signaling structure, the apical ectodermal ridge (AER) forms. It signals mesenchyme

to proliferate and the limb grows.

Removal of the AER inhibits outgrowth of the limbTransplantation of a second AER duplicates the limb; diplopodia. The signals responsible for this are fibroblast growth factors.


Proximodistal (PD) growth - regulated by AER (Fgfs):

Embryological manipulation in the developing chick limb established that the apical ectodermal ridge (AER) is necessary for maintenance of PD outgrowth in the limb bud. Removal of the AER at early stages causes severe truncations of the limb skeletal elements. Progressively later removal of the AER causes progressively more distal truncations of limb elements.

Removal of AER in chick at progressively later HH stages of development


Removal of AER: arrests limb development at stage at which it was removed


Fgf4/Fgf8 double mutants(Sun, et al., 2002):

No limb outgrowth, BUTearly patterning markers are unperturbed.

Thus, Fgf’s only permissive for outgrowth, apparently not important for early patterning.

Sun, et al., Nature, 2002Source Undetermined

Molecular control of proximodistal (PD) growth:

Identical results have been achieved in mouse genetic models.

Genetic removal of Fgf8 and Fgf4 in the AER of developing mouse limbs at progressively earlier time points cause more severe (more proximal) truncations, proving that Fgf4 and Fgf8 represent the AER activity required for PD outgrowth.

Important Note: With complete removal of all AER FGF expression, NO limb skeletal elements are formed BUT the limb bud is established at the normal time and location and early markers are expressed normally.

Therefore, FGFs are essential for limb bud outgrowth but DO NOT appear to be important for limb patterning.


Anterior-posterior (AP) patterning: Early embryological experimentation in chick established that an area at the posterior, distal margin of the emerging limb bud, when grafted to an anterior location, was capable of causing mirror-image duplications of the digits. This region was termed Zone of Polarizing Activity (ZPA).

Source Undetermined

Sonic hedgehog (Shh) expression was shown to be coincident with the ZPA region and Shh soaked beads could reproduce the digit phenotype.

Shh


Such disturbances are not uncommon in humans:



Any cells capable of expressing Shh were able to reproduce this phenotype.

Cells contributing to the phenotype were from host and donor cells - example of a cell non-autonomous defect

Source Undetermined

Shh induces the conversion of Gli3R to Gli3A;

results in a gradient of R/A across the AP axis of the limb bud

Conc.

Gli3

Act.

Rep.

Source Undetermined


Loss of Shh results in single stylopod, single zeugopod, single digit - consistent with idea that Shh is critical AP patterning molecule…

However, biochemical work was showing that Gli3 was the transcriptional modulator of Shh function.

Gli3 loss-of-function resulted in polydactyly.

Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity. Nature.com. August, 2002, Volume 418.

Loss of Shh results in single stylopod, single zeugopod, single digit - consistent with idea that Shh is critical AP patterning molecule…

However, biochemical work was showing that Gli3 was the transcriptional modulator of Shh function.

Gli3 loss-of-function resulted in polydactyly.

Shockingly, Shh/Gli3 double mutants look identical to Gli3 nulls!!

Shh only modulates inherent polydactylous limb ‘ground state.’Shh and Gli3 are dispensable for limb skeleton formation but regulate digit

number and identity. Nature.com. August, 2002, Volume 418.

Molecular control of anteroposterior (AP) patterning:

In mice,- Loss of Shh causes a reduction in elements to 1 stylopod element, 1 zeugopod element and a single digit, digit #1.- Loss of Gli3, which is downstream of Shh in many systems, causes the other extreme, synpolydactyly (supernumerary digits with no discernible pattern).- Double mutants of Shh and Gli3 phenocopy Gli3 mutants, demonstrating that Shh’s activity is largely through its downstream transcription factor, Gli3.

-Important Note: The Shh/Gli3 system does NOT affect the ability of the skeletal elements to form.


Ectoderm (AER) promotes outgrowth signals, but mesoderm controls limb identity.


Fgf beads are capable of inducing ectopic limbs. The identity of the ectopic limb is dependent on position within the flank. Very rarely a chimeric ectopic limb is formed.


Forelimb/Hindlimb Identity:Fgf beads are capable of inducing ectopic limbs. The identity of the ectopic limb is dependent on position within the flank. Very rarely a chimeric ectopic limb is formed.


Expression of Tbx4defines lower limb.

Expression of Tbx5defines upper limb.

Post-specification: What molecular signals distinguish forelimb from hindlimb are poorly defined

Source Undetermined

Experimentally, it has been determined that the flank region between the fore- and hindlimb, but not anterior or posterior to it, can be induced to form limbs (Fgfs, Tbx4 and Tbx5).

Tbx5

Tbx4

Whether the ectopic limb becomes forelimb or hindlimb depends on WHERE in the flank it is induced.

Identity of ectopic limb is correlated with expression of Tbx.

Source Undetermined

The correlation of Tbx5/4 expression with some overexpression results in chick led to the hypothesis that Tbx5/4 control the differential identity of forelimbs and hindlimbs.

Elegant genetic work has shown this is NOT TRUE!!!

Developmental Cell, Vol. 8, 75-84, January, 2005

S

Z

A

S

Z

A

HINDLI

MBS

FORELI

MBS

Hoxa13/Hoxd13

Hoxa13/Hoxd13

Hoxa11/Hoxd11

Hox9PHox10P( )

Patterning of the limb elements: Hox9 through Hox13 paralogous groups are responsible for establishing morphological pattern

Hox10

Hox11

Hox13

S

Z

A

Fromental-Ramain, et al, 1996

Z

Hoxa11/Hoxc11/Hoxd11

Hoxa10/Hoxc10/Hoxd10

hl

hlfl

fl & hl

Wellik and Capecchi, Science, 2003

Failure to develop a limb: amelia

Loss of AER or FGF signalling

Source Undetermined

Polydactyly: duplication of digits: inherent in mesoderm

Disrupted Shh/Gli3 functionSource Undetermined

Lack of BMP4, or expression of an inhibitor in the interdigital space, results in fusions, syndactyly or webbing of fingers and toes

Source Undetermined Sadler. Langman’s Medical Embryology. Lippincott 2004. 10th ed.

• Meromelia Absence of part of a limb (disrupted Fgf signaling)

• Amelia Absence of an entire limb (loss of Fgf signaling)

• Phocomelia Short, poorly formed limb (partial loss of Fgf, Hox disruption)

• Ectrodactyly Absence of fingers or toes (Hox13, late loss of Fgf signalling)

• Polydactyly Extra digits (disruption of Shh pathway)

• Syndactyly Fusion of digits (Bmp disruption)

• Adactyly Absence of digits (late loss of Fgf)

Limb malformations

47 days

11 weeks

A myriad of complex genetic interactions result in the formation and proper development of the human limb….

Source Undetermined

Source Undetermined

Additional Source Information

for more information see: http://open.umich.edu/wiki/CitationPolicy

Slide 3: Carlson: Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.Slide 4: Source UndeterminedSlide 5: Gilbert. Developmental Biology, Sinauer and Associates. Eighth EditionSlide 6: Gilbert. Developmental Biology, Sinauer and Associates. Eighth EditionSlide 7: Carlson: Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.Slide 8: Gilbert. Developmental Biology, Sinauer and Associates. Eighth EditionSlide 9: Gilbert. Developmental Biology, Sinauer and Associates. Eighth Edition (Both images)Slide 10: Gilbert. Developmental Biology, Sinauer and Associates. Eighth EditionSlide 11: Source UndeterminedSlide 12: Source UndeterminedSlide 13: Source UndeterminedSlide 14: Gilbert. Developmental Biology, Sinauer and Associates. Eighth EditionSlide 15: Gilbert. Developmental Biology, Sinauer and Associates. Eighth EditionSlide 16: Source UndeterminedSlide 17: Gilbert. Developmental Biology, Sinauer and Associates. Eighth EditionSlide 18: Deneen WellikSlide 19: Source UndeterminedSlide 20: Carlson: Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.; Source UndeterminedSlide 21: Source UndeterminedSlide 22: Source UndeterminedSlide 23: Deneen WellikSlide 24: Wellik and Capecchi, Science, 2003Slide 25: Gilbert. Developmental Biology, Sinauer and Associates. Eighth EditionSlide 26: Carlson: Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.Slide 28: Sadler. Langman’s Medical Embryology. Lippincott 2004. 9th ed.; Sadler. Langman’s Medical Embryology. Lippincott 2004. 9th ed.Slide 29: Sadler. Langman’s Medical Embryology. Lippincott 2004. 9th ed.Slide 30: Sadler. Langman’s Medical Embryology. Lippincott 2004. 10th ed.Slide 31: Sadler. Langman’s Medical Embryology. Lippincott 2004. 10th ed.Slide 32: Sadler. Langman’s Medical Embryology. Lippincott 2004. 10th ed.Slide 36: Source Undetermined; Source UndeterminedSlide 37: Carlson: Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.Slide 38: Sadler. Langman’s Medical Embryology. Lippincott 2004. 9th ed.Slide 39: Sadler. Langman’s Medical Embryology. Lippincott 2004. 10th ed.Slide 40: Sadler. Langman’s Medical Embryology. Lippincott 2004. 9th ed.Slide 41: Gilbert. Developmental Biology, Sinauer and Associates. Eighth EditionSlide 42: Gilbert. Developmental Biology, Sinauer and Associates. Eighth EditionSlide 43: Carlson: Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.

Gilbert. Developmental Biology, Sinauer and Associates. Eighth EditionSlide 46: Cliff TaubmanSlide 47: Gilbert. Developmental Biology, Sinauer and Associates. Eighth EditionSlide 48: Source UndeterminedSlide 49: Source UndeterminedSlide 50: Niswander. Pattern Formation: Old models out on a limb. Nature.com. February 2003, volume 4.Slide 51: Gilbert. Developmental Biology, Sinauer and Associates. Eighth EditionSlide 52: Sadler. Langman’s Medical Embryology. Lippincott 2004. 9th ed.Slide 53: Carlson: Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.Slide 54: Sadler. Langman’s Medical Embryology. Lippincott 2004. 10th ed.Slide 55: Sadler. Langman’s Medical Embryology. Lippincott 2004. 9th ed.Slide 56: Sadler. Langman’s Medical Embryology. Lippincott 2004. 9th ed.Slide 57: University of the Basque Country Press, 1990.Slide 58: Gilbert. Developmental Biology, Sinauer and Associates. Eighth EditionSlide 59: Carlson: Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.Slide 60: Source UndeterminedSlide 61: Gilbert. Developmental Biology, Sinauer and Associates. Eighth EditionSlide 62: Gilbert. Developmental Biology, Sinauer and Associates. Eighth EditionSlide 63: Carlson: Human Embryology and Developmental Biology. Elsevier, 2004. 3rd. Ed.Slide 64: Source Undetermined; Sun, et al., Nature, 2002Slide 65: Niswander. Pattern Formation: Old models out on a limb. Nature.com. February 2003, volume 4.Slide 66: Source UndeterminedSlide 67: Gilbert. Developmental Biology, Sinauer and Associates. Eighth EditionSlide 68: Sadler. Langman’s Medical Embryology. Lippincott 2004. 10th ed.Slide 69: Source UndeterminedSlide 70: Source Undetermined; Gilbert. Developmental Biology, Sinauer and Associates. Eighth EditionSlide 71: Litingtung, Dahn, Li, Fallon, Chiang. Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity. Nature.com. August, 2002, Volume 418.Slide 72: Litingtung, Dahn, Li, Fallon, Chiang. Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity. Nature.com. August, 2002, Volume 418.Slide 73: Niswander. Pattern Formation: Old models out on a limb. Nature.com. February 2003, volume 4.Slide 74: Gilbert. Developmental Biology, Sinauer and Associates. Eighth EditionSlide 75: Gilbert. Developmental Biology, Sinauer and Associates. Eighth EditionSlide 76: Gilbert. Developmental Biology, Sinauer and Associates. Eighth EditionSlide 77: Source UndeterminedSlide 78: Source Undetermined Slide 79: Developmental Cell, Vol 8, 75-84, January, 2005Slide 80: Wellik and Capecchi, Science, 2003; Fromental-Ramain, et al, 1996Slide 81: Source UndeterminedSlide 82: Source UndeterminedSlide 83: Source Undetermined; Sadler. Langman’s Medical Embryology. Lippincott 2004. 10th ed.Slide 85: Source Undetermined

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