Biología de la Diferenciación Celular

Tema 3

Primeras fases del desarrollo embrionario.

Linaje celular en el desarrollo de los
vertebrados
Primeras fases del desarrollo embrionario. Linaje
celular en el desarrollo de los vertebrados

1. Primeras fases del desarrollo embrionario

2. Patrones de segmentación

3. Blastulación

4. Implantación

5. Gastrulación

6. Neurulación

7. Diferenciación de las capas germinativas primarias.

Linaje celular en el desarrollo de los vertebrados

8. Defectos congénitos y diagnóstico prenatal

1. Primeras fases del desarrollo embrionario
 Mecanismos universales del desarrollo animal

Producción de muchas Creación de células con diferentes

células a partir de una características en distintas posiciones

Organización de las
Coordinación del comportamiento de
células para formar
una célula en relación a sus vecinas
tejidos y órganos
Figure 22-1. Alberts
et al., 2008.
Primeros estadíos del desarrollo embrionario humano
Desarrollo de
los tejidos
embrionarios
humanos
Ovulación
 Fecundación

Desarrollo de
los tejidos
embrionarios
humanos
Fecundación
Segmentación
 Desarrollo embrionario humano

Cigoto Estadío de 2 células (30 horas)

 Desarrollo embrionario de ratón
Estadío de 2 células Estadío de 4 células Estadío de 8 células

Compactación Mórula Blastocisto

Figure 11.22. The cleavage of a single mouse embryo in vitro. (A) 2-cell stage. (B) 4-cell stage. (C) Early 8-cell stage. (D) Compacted 8-
cell stage. (E) Morula. (F) Blastocyst. (Gilbert, 2003).
 Gemelos monocigóticos

Figure 11.32. Diagram showing the timing of human monozygotic twinning with relation to extraembryonic membranes. (A) Splitting
occurs before the formation of the trophoblast, so each twin has its own chorion and amnion. (B) Splitting occurs after trophoblast formation
but before amnion formation, resulting in twins having individual amnionic sacs but sharing one chorion. (C) Splitting after amnion
formation leads to twins in one amnionic sac and a single chorion. (After Langman 1981)..)(Gilbert., 2003).
2. Patrones de segmentación
 Segmentación
División meridional División rotacional

Figure 11.21. Comparison of early cleavage in (A) echinoderms and amphibians (radial cleavage) and (B) mammals (rotational cleavage).
Nematodes also have a rotational form of cleavage, but they do not form the blastocyst structure characteristic of mammals. (Gilbert., 2003).
 Segmentación en el embrión de rana

División meridional

Figure 10.2. Scanning electron micrographs of the cleavage of a

frog egg. (A) First cleavage. (B) Second cleavage (4 cells). (C)
Fourth cleavage (16 cells), showing the size discrepancy
between the animal and vegetal cells after the third division.
(Gilbert,, 2003).
 Desarrollo embrionario humano

3 días post-fecundación 4 días post-fecundación

(16 células)
Compactación
Compactación en el embrión de ratón de 8 células

Embrión no compactado Embrión compactado

Figure 11.23. Scanning electron micrographs of (A) uncompacted and (B) compacted 8-cell mouse embryos. (Gilbert, 2003).
 Estadíos iniciales del desarrollo del ratón

Compactación

Figure 22-88. The early stages of mouse development. The zona pellucida is a jelly capsule from which the embryo escapes after a few
days, allowing it to implant in the wall of the uterus. (Alberts et al., 2008).
 Diferenciación de la mórula de 16 células

Trofoectodermo o trofoblasto
Æ Capa externa de células provenientes de la división de las
células de la capa exterior de la mórula
Æ Genera las células trofoblásticas del corion

Masa celular interna

Æ Núcleo interno de células
Æ Genera todos los tejidos embrionarios y estructuras asociadas:
saco vitelino, alantoides y amnios (tejidos extraembrionarios)
Æ Libera FGF-4 para ayudar a la embriogénesis y regular la
proliferación y diferenciación del trofoectodermo
3. Blastulación
 Blastulación

Desarrollo de
los tejidos
embrionarios
humanos
Formación del blastocisto
 Formación del blastocisto
Cavitación

Masa celular interna

Blastocele

Trofoblasto
Cavitación

Días 5 a 6 del desarrollo embrionario humano

 Estadíos iniciales del desarrollo del ratón

Blastulación
Figure 22-88. The early stages of mouse development. The zona pellucida is a jelly capsule from which the embryo escapes after a few
days, allowing it to implant in the wall of the uterus. (Alberts et al., 2008).
 Desarrollo temprano en el embrión de ratón y humano
Humano

Ratón

2 células 4 células Mórula Blastocisto

Figure 22-89. Scanning electron micrographs of the early mouse embryo. The zona pellucida has been removed. (A) Two-cell stage. (B) Four-cell stage (a polar
body is visible in addition to the four blastomeres see Figure 20-22). (C) Eight-to-sixteen-cell morula compaction occurring. (D) Blastocyst. (Alberts et al., 2008).
 Desarrollo embrionario humano

Formación del blastocisto

5 días post-fecundación 6 días post-fecundación

Escape del blastocisto de la zona pelúcida
Liberación del blastocisto de la zona pelúcida

Figure 11.25. Mouse blastocyst hatching from the zona pellucida. (Gilbert, 2003).
Liberación del blastocisto de la zona pelúcida
 Liberación de la zona pelúcida

Trofoblasto
Æ Na+/K+ ATPasa: entrada de Na+ y H2O en el blastocele

Æ Estripsina: lisis de la matriz fibrilar de la membrana pelúcida

Æ Integrinas: unión a fibras de colágeno, laminina y fibronectina del endometrio

Æ Sintetiza heparán-sulfato

Æ Sintetiza colagenasa, estromelisina y activador del plasminógeno

Endometrio
Æ Fibras de colágeno, laminina, fibronectina y ácido hialurónico

Æ Receptores de heparán-sulfato
 Requerimientos nutritivos del embrión

Embrión en las primeras divisiones mitóticas

Æ Piruvato
Æ Lactato
Æ Aminoácidos

Blastocisto
Æ Glucosa (transportador GLUT-8, receptor de IGF-1)
4. Implantación
Implantación
Desarrollo de
los tejidos
embrionarios
humanos

Implantación
 Implantación del blastocisto de mamífero

Mono Rhesus
Ratón of the mammalian blastocyst into the uterus. (A) Mouse blastocysts entering the uterus.
Figure 11.24. Implantation
(B) Initial implantation of the blastocyst in a rhesus monkey. (Gilbert., 2003).
Implantación del blastocisto humano
 Desarrollo embrionario en mamíferos

Masa celular interna

Æ Epiblasto = ectodermo embrionario o primitivo:
origina todas las células del cuerpo del embrión
constituido por células pluripotentes
gastrulación: origina las tres capas germinativas primarias

Æ Hipoblasto: origina el endodermo primitivo

gastrulación: origina el endodermo parietal y visceral

Trofoblasto
 Formación de tejidos en el embrión humano de 7-8 días

Masa celular interna Trofoblasto

Epiblasto Citotrofoblasto Æ Villi
Hipoblasto Sincitiotrofoblasto

Figure 11.27. Tissue formation in the human embryo between days 7 and 11. (A, B) Human blastocyst immediately prior to gastrulation.
The inner cell mass delaminates hypoblast cells that line the blastocoel, forming the extraembryonic endoderm of the primitive yolk sac and a
two-layered (epiblast and hypoblast) blastodisc similar to that seen in avian embryos. The trophoblast in some mammals can be divided into
the polar trophoblast, which covers the inner cell mass, and the mural trophoblast, which does not. The trophoblast divides into the
cytotrophoblast, which will form the villi, and the syncytiotrophoblast, which will ingress into the uterine tissue. (C) Meanwhile, the epiblast
splits into the amnionic ectoderm (which encircles the amnionic cavity) and the embryonic epiblast. The adult mammal forms from the cells of
the embryonic epiblast. (D) The extraembryonic endoderm forms the yolk sac. (Gilbert, 2003).
 Formación de tejidos en el embrión humano de 9-11 días

Formación de la cavidad amniótica

Figure 11.27. Tissue formation in the human embryo between days 7 and 11. (A, B) Human blastocyst immediately prior to gastrulation.
The inner cell mass delaminates hypoblast cells that line the blastocoel, forming the extraembryonic endoderm of the primitive yolk sac and a
two-layered (epiblast and hypoblast) blastodisc similar to that seen in avian embryos. The trophoblast in some mammals can be divided into
the polar trophoblast, which covers the inner cell mass, and the mural trophoblast, which does not. The trophoblast divides into the
cytotrophoblast, which will form the villi, and the syncytiotrophoblast, which will ingress into the uterine tissue. (C) Meanwhile, the epiblast
splits into the amnionic ectoderm (which encircles the amnionic cavity) and the embryonic epiblast. The adult mammal forms from the cells of
the embryonic epiblast. (D) The extraembryonic endoderm forms the yolk sac. (Gilbert, 2003).
5. Gastrulación
Desarrollo de los
tejidos
embrionarios
humanos

Gastrulación
Goosecoid
T
Evx-2
Wall
Follistatin yolk
sac

Late in the second week of human gestation, the embryo has two cell layers, an epiblast and a hypoblast.
(The mouse embryo in the micrograph on the top has a more curved form at this stage than the human, as
shown in the diagram on the bottom)
Gastrulación humana

Embrión humano
de 15 días

Figure 11.28. Amnion structure

and cell movements during human
gastrulation. (A) Human embryo
and uterine connections at day 15
of gestation. In the upper view, the
embryo is cut sagittally through
the midline; the lower view looks
down upon the dorsal surface of
the embryo. (Gilbert., 2003).
 Gastrulación humana

Embrión humano de 14-16 días

Figure 11.28. Amnion structure and cell movements during human gastrulation. (B) The movements of the epiblast cells through
the primitive streak and Hensen's node and underneath the epiblast are superimposed on the dorsal surface view. At days 14 and
15, the ingressing epiblast cells are thought to replace the hypoblast cells (which contribute to the yolk sac lining), while at day 16,
the ingressing cells fan out to form the mesodermal layer. (Gilbert., 2003).
Movimientos celulares en la gastrulación de ratón

Embrión de ratón de 7 días

(16 días en humanos)

The epiblast cells at the caudal

midline (primitive streak) invaginate.
This process is termed gastrulation.
Invagination of these cells results in
formation of the mesoderm and
replacement of some of the hypoblast
cells to produce the definitive
endoderm.

Figure 4-3. Sadler, 2004

Movimientos celulares en la gastrulación de ratón

Embrión de ratón de 7 días

(16 días en humanos)
Figure 4-3. Sadler, 2004
Movimientos celulares en la gastrulación de ratón

Figure 4-3. Sadler, 2004

Gastrulación

A cut through the embryo illustrates the three germ layers:

ectoderm (formerly referred to as epiblast), mesoderm, and
endoderm.
 Gastrulación

Ectodermo

Mesodermo

Endodermo

Note the ectoderm,

ectoderm, the mesoderm,
mesoderm,
and the embryonic endoderm.
endoderm.
The mesoderm in the ventral
midline is the notochordal plate.
plate. In
the rostral midline,
midline, the ectoderm
and endoderm are opposed.
opposed. The
endoderm in this location forms the
prechordal plate.
plate.
Placa notocordal
Formación de la
notocorda

The notochord extends

in the midline from the
prechordal plate,
caudally to the primitive
streak.
 Formación de la notocorda en el ratón
Intestino primitivo (endodermo)

Notocorda
Figure 11.29. Formation of the notochord in the mouse. (A) The ventral surface a the 7.5-day mouse embryo, seen by scanning electron microscopy. The presumptive
notochord cells are the small, ciliated cells in the midline that are flanked by the larger endodermal cells of the primitive gut. The node (with its ciliated cells) is seen at
the bottom. (B) The formation of the notochord by the dorsal infolding of the small, ciliated cells. (Gilbert., 2003).
Embrión humano de 40 días de gestación

Figure 11.30. Human embryo and placenta after 40 days of gestation. The embryo lies within the
amnion, and its blood vessels can be seen extending into the chorionic villi. The small sphere to the
right of the embryo is the yolk sac. (Gilbert, 2003).
 Fecundación

Blastulación

Implantación

Gastrulación

Sumario
Sumario
Desarrollo
Desarrollode
delos
los
tejidos
tejidosembrionarios
embrionarios
humanos
humanos
6. Neurulación
 Formación del tubo neural

Tubo neural
 Formación del
tubo neural

Figure 12.3. Primary neurulation: neural tube

formation in the chick embryo. (A, 1) Cells of
the neural plate can be distinguished as
elongated cells in the dorsal region of the
ectoderm. Folding begins as the medial neural
hinge point (MHP) cells anchor to notochord
and change their shape, while the presumptive
epidermal cells move towards the center.
(B, 2) The neural folds are elevated as
presumptive epidermis continues to move
toward the dorsal midline. (C, 3) Convergence
of the neural folds occurs as the dorsolateral
hinge point (DLHP) cells become wedge-
shaped and epidermal cells push toward the
center. (D, 4) The neural folds are brought into
contact with one another, and the neural crest
cells link the neural tube with the epidermis.
The neural crest cells then disperse, leaving
the neural tube separate from the epidermis.
(Gilbert., 2003).
Formación del tubo neural

Embrión de pollo de dos días

Figure 22-97. Formation of the neural tube. The scanning

electron micrograph shows a cross section through the trunk
of a 2-day chick embryo. The neural tube is about to close
and pinch off from the ectoderm; at this stage it consists (in
the chick) of an epithelium that is only one cell thick.
(Alberts et al., 2008).
 Formación del tubo neural
Placa del techo
“Roof plate”

Placa del suelo Notocorda

“Floor plate”
 Neurulación

Pliegues neurales

Boca

Corazón

Surco
neural
Intestino
Somitas

Figura 5-6. Vistas dorsal y ventral de

un embrión de ratón de 8 días,
correspondiente a un embrión humano
de 22 días (Sadler., 2004).

A Ventral view illustrates:

Embrión de ratón de ocho días
the stomodeum (primitive oral cavity),
the heart in the pericardial cavity,
the anterior intestinal portal leading to
the foregut,
and the posterior intestinal portal
leading to the hindgut.
 Formación del tubo neural
Prosencéfalo

Corazón

Species: Mouse
Day Gestation: 8
Approx. Human Age: 22 Days
Intestino View: Ventral

By the beginning of the 4th week of human development, a ventral

view illustrates several important structures:

Æ the anterior-most aspect of the brain (forebrain, prosencephalon)

Æ the heart (which is just beginning to beat)

Æ the foregut region dorsal to the heart

Æ and the developing hindgut

 Neurulación

Surco
neural

Somitas

Fusion of the neural folds is

initiated at the future upper
cervical levels, progressing both
rostrally and caudally to form the
neural tube.
Formación del tubo neural

Células escamosas
Ectodermo

Células columnares
Tubo neural
Note the squamous (flat) surface ectodermal cells
and the columnar cells comprising the neural tube.
 Formación del tubo neural

Neuroporo anterior

A frontal view illustrates the closing

anterior neuropore and the stomodeum.

Species:
Species: Mouse
The anterior neural folds close during the later part of the 4th week
Day Gestation:
Gestation: 9
of human development.
Approx.
Approx. Human Age:
Age: 25 Days
View:
View: Frontolateral
Formación del tubo neural

Neuroporo posterior

Species: Mouse
Day Gestation: 9
Approx.Human Age: 28 Days
View: Lateral

The posterior neuropore closes about 2 days

after the anterior neuropore, when the embryo
is tightly curved ventrally and an upper limb
bud is evident.
7. Diferenciación de las capas germinativas
primarias. Linaje celular en el desarrollo
de los vertebrados
Desarrollo de los tejidos embrionarios humanos
y de mono

Figure 11.26. Schematic diagram showing the derivation of tissues in human and rhesus monkey embryos. (Gilbert, 2003).
Diferenciación
de los tejidos
humanos
 Tejidos derivados de las hojas germinativas
primarias

Ectodermo
Sistema nervioso central (cerebro y médula espinal)
Sistema nervioso periférico
Superficie externa o piel del organismo, que incluye pelo y uñas
Epitelio sensorial de oído, nariz y ojo
Córnea y cristalino del ojo
Epitelio que cubre las cavidades bucal, nasal y del canal anal
Epitelio de la glándula pineal, glándula pituitaria y médula adrenal
Células de la cresta neural (estructuras faciales, melanocitos y ganglios
espinales dorsales)
Glándulas subcutáneas
Glándula mamaria
Esmalte dental
 Tejidos derivados de las hojas germinativas
primarias

Mesodermo
Músculo esquelético, liso y cardíaco
Estructuras del sistema urogenital: riñones, uréteres, gónadas y tractos
reproductivos
Corazón, sangre, médula ósea y vasos y células linfáticas
Bazo
Tejido graso
Hueso y cartílago
Otros tejidos conectivos
Membranas serosas que revisten las cavidades pericárdica, pleural y
peritoneal
Corteza de la glándula suprarrenal
 Tejidos derivados de las hojas germinativas
primarias

Endodermo
Epitelio del tracto digestivo completo (excepto la boca y el canal anal)
Epitelio del tracto respiratorio
Estructuras asociadas con el tracto digestivo: hígado y páncreas
Glándulas tiroides, paratiroides y timo
Parénquima de amígdalas
Epitelio del tracto reproductivo
Epitelio de la uretra y vejiga
Revestimiento epitelial de la caja del tímpano y trompa de Eustaquio
8. Defectos congénitos y diagnóstico prenatal
 Tipos de anomalías
- Malformaciones
Se producen durante la organogénesis. Se originan por factores ambientales y/o genéticos,
que actúan independientemente o de forma simultánea

- Disrupciones
Provocan alteraciones morfológicas de las estructuras una vez formadas y se deben a
procesos destructivos. Ej.: accidentes vasculares que producen atresias intestinales,
defectos producidos por bandas amnióticas, etc.

- Deformaciones
Obedecen a fuerzas mecánicas que moldean al feto durante períodos de tiempo prolongado.
Ej.: pie zambo por compresión en la cavidad amniótica

- Síndromes
Grupo de anomalías que se presentan al mismo tiempo y que tienen una causa específica
común diagnosticada y cuya recurrencia se conoce

- Asociaciones
Aparición no aleatoria de dos anomalías o más que se presentan juntas con más frecuencia
de lo que cabría esperar por simple probabilidad y cuya causa no ha sido determinada
 Diagnóstico prenatal

- Ecografía de alta resolución

- Amniocentesis

- Biopsia de vellosidades coriónicas

- Estudio del suero materno

- Funiculocentesis
Desarrollo fetal
GEMELOS SIAMESES

RX que ilustra la
hiperextensión de la
(a). Siameses toraco-onfalópagos. Corte
columna cervical
transversal a nivel del tórax. Las cavidades
cardíacas se encuentran unidas

Nacimiento: unión
(b). Corte transversal a nivel abdominal. a nivel del tórax y
Hay unión clara compartiendo hígado abdomen
Drogas y químicos Radiaciones ionizantes (Rayos X)
Alcohol

Aminoglucósidos Hipertermia
Aminopterina

Agentes antitiroideos Microorganismos infecciosos

Bromina Virus Coxsackie
Cortisona Citomegalovirus
Dietilestilbestrol Herpes simple
Difenilhidantoína Parvovirus
Heroína Rubéola
Plomo Toxoplasma gondii (Toxoplasmosis)
Metilmercurio Treponema pallidum (Sífilis)
Penicilamina

Ácido retinoico Alteraciones metabólicas maternas

Estreptomicina Enfermedad autoinmune (incompatibilidad Rh, etc.)
Tetraciclina Diabetes
Talidomida Deficiencias en la dieta, malnutrición
Trimetadiona Fenilcetonuria
Ácido valproico
Warfarina
Efecto del etanol sobre el desarrollo del SNC

Figure 21.21. Comparison of a brain from an infant with fetal alcohol syndrome (left) with a brain from a
normal infant of the same age (right). The brain from the infant with FAS is significantly smaller, and the
pattern of convolutions is obscured by glial cells that have migrated over the top of the brain. (Photographs
courtesy of S. Clarren.) (Gilbert, 2003).
Efecto del etanol sobre el desarrollo del SNC

Control Etanol Etanol + superóxido dismutasa

Figure 21.22. Possible mechanisms producing

fetal alcohol syndrome. (A-C) Cell death caused
by ethanol-induced superoxide radicals. Staining
with Nile blue sulfate reveals areas of cell death.
(A) Control 9-day mouse embryo head region. (B)
Head region of ethanol-treated embryo, showing
areas of cell death. (C) Head region of 9-day
embryo treated with both ethanol and superoxide
dismutase, an inhibitor of superoxide radicals. The
superoxide inhibitor prevents the alcohol-induced
cell death. (D) The inhibition of L1-mediated cell
adhesion by ethanol. (A-C from Kotch et al. 1995;
photographs courtesy of K. Sulik; D after
Ramanathan et al. 1996.) (Gilbert, 2003).
 Alteraciones del desarrollo causadas por un agente
ambiental

Figure 1.16. Developmental anomalies caused by an environmental agent. (A) Phocomelia, the lack of proper limb development,
was the most visible of the birth defects that occurred in many children whose mothers took the drug thalidomide during pregnancy.
(B) Thalidomide disrupts different structures at different times of human development. (Photograph © Deutsche Presse/Archive
Photos; B after Nowack 1965.) (Gilbert, 2003).
Alteraciones del desarrollo

Pie zambo congénito

José de Ribera. “El muchacho

con el pie zambo”
 Teratogénesis del ácido retinoico

Figure 11.39. Mouse embryos cultured at day 8 in control medium (A, C) or in medium containing retinoic acid (B, D). At day 10 (A, B),
the first pharyngeal arch of the treated embryos has a shortened and flattened appearance and has apparently fused with the second
pharyngeal arch. At day 17 (C, D), craniofacial malformations can be seen in the neural crest-derived cartilage of the treated embryos.
Meckel's cartilage has been completely displaced from the mandibular (lower jaw) to the maxillary (upper mouth) region, and the malleus
and incus cartilages have not formed. (E) In some cases, RA exposure causes the loss of the lumbar, sacral, and caudal vertebrae. (A and B
from Goulding and Pratt 1986; C and D from Morriss-Kay 1993; E from Kessel 1992, photographs courtesy of the authors.)(Gilbert.,
2003).
 Alteraciones del desarrollo causadas por mutaciones
genéticas

Figure 1.53. Developmental anomalies caused by genetic mutation. (A) Piebaldism in a human infant. This genetically produced condition
results in sterility, anemia and underpigmented regions of the skin and hair, along with defective development of gut neurons and the ear.
Piebaldism is caused by a mutation in the KIT gene. The Kit protein is essential for the proliferation and migration of neural crest cells, germ
cell precursors, and blood cell precursors. (B) A piebald mouse with a mutation of the Kit gene. Mice provide important models for studying
human developmental diseases. (Photographs courtesy of R. A. Fleischman.) (Alberts et al., 2008).
Patologías del desarrollo causadas por alteraciones
en vías de señalización celular

Figure 6.25. Head of a cyclopic lamb born of a ewe who had eaten Veratrum californicum early in pregnancy. The cerebral
hemispheres fused, forming only one central eye and no pituitary gland. The jervine alkaloid made by this plant inhibits
cholesterol synthesis, which is needed for Hedgehog production and reception. (Gilbert, 2003).