Download (eg, cleft lip, polydactyly).

与发育相关的基因
张咸宁
[email protected]
Tel：13105819271; 88208367
Office: A705, Research Building
2014/09
出生缺陷（Birth defect）：即先天性疾病
• Malformation畸形 is a primary morphologic defect of an organ or body
part resulting from an intrinsically abnormal developmental process (e.g.,
cleft lip, polydactyly).
• Dysplasia发育异常 is a primary defect involving abnormal organization of
cells into tissue (e.g., vascular malformation).
• Sequence序列征 is a primary defect with its secondary structural changes
(e.g., Pierre Robin sequence, a disorder in which a primary defect in
mandibular下颌骨 development produces a small jaw, secondary
glossoptosis舌后坠, and a cleft palate)
• Syndrome综合征 is a pattern of multiple primary malformations with a
single etiology (e.g., trisomy 13 syndrome).
• Deformation变形 is alteration of the form, shape, or position of a normally
formed body part by mechanical forces. It usually occurs in the fetal period,
not in embryogenesis. It is a secondary alteration. It can be extrinsic, as in
oligohydramnios羊水过少 (reduced amniotic fluid), or intrinsic, as in
congenital myotonic dystrophy.
• Disruption畸化 is a morphological defect of an organ, part of an organ, or a
larger region of the body resulting from the extrinsic breakdown of, or
interference with, an originally normal developmental process. It is a
secondary malformation (e.g., secondary limb defect resulting from a
vascular event).
Developmental Gene Families
• Model animals: Drosophila melanogaster, frog,
mouse, chick, zebra-fish…
• Transcription factors can switch genes on and off
by activating or repressing gene expression.
• Fundamental embryological processes:
induction (the process in which extracellular
signals give rise to a change from one cell fate to
another in a particular group of cells),
segmentation, migration, differentiation, and PCD
(apoptosis).
• These processes are mediated by growth factors,
cell receptors, and chemicals (morphogens).
Transcription factors
• These gene regulatory proteins have a
transcriptional activation domain and a
DNA-binding domain.
• 4 types of DNA-binding domain: helixturn-helix, zinc finger, leucine zipper,
helix-loop-helix.
Early Patterning
• Induction of the mesoderm-the initiation, maintenance,
and subsequent patterning of this layer-involves several
key families of signaling factors.
• The Nodal family is involved in initiation, FGFs
(fibroblast growth factors) and WNTs (wingless) are
involved in maintenance, and BMPs (bone
morphogenetic proteins) are involved in patterning the
mesoderm.
• The WNT pathway has two main branches: β-catenindependent (canonical) , independent of β-catenin.
• E.g., Mutated WNT10A in man results in a form of
ectodermal dysplasia (odonto-onychodermal dysplasia).
The TGF-β (transforming growth factorβ ) Superfamily in Development and
Disease
• 33 members of this cytokine family.
• 2 groups: (1) the BMPs, (2) the TGF-βs, activins,
nodal, and myostatin, acting through various SMAD
proteins.
• Regulation of the cell cycle, cell migration, cell size,
gastrulation and axis specification, and metabolic
processes.
• In relation to health and disease, there are
consequences for immunity, cancer, heart disease,
diabetes, and Marfan syndrome.
Fig. 6b
Somatogenesis（体质发生） and
the Axial Skeleton（中轴骨骼）
• Wnt and FGF signals play vital roles in the specification
of the presomitic mesoderm（前体节中胚层）.
• The key pathway here is notch-delta signaling and the
‘oscillation clock’-a precise, temporally defined wave
of cycling gene expression (c-hairy in the chick, lunatic
fringe and hes genes in the mouse) that sweeps from the
tail-bud region in a rostral（嘴的） direction and has a
key role in the process leading to the defining of somite
boundaries.
• E.g., presenile dementia (presenilin-1), which is
dominantly inherited, and spondylocostal dysostosis (脊
椎肋骨发育不全。delta-like-3, mesoderm posterior-2,
lunatic fringe, and hairy enhancer of split-7), which is
recessively inherited.
The Sonic Hedgehog-Patched GLI
Pathway
• The Sonic hedgehog gene (SHH) induces cell
proliferation in a tissue-specific distribution and is
expressed in the notochord, the brain, and the zone
of polarizing activity of developing limbs.
• The key intracellular targets are the GLI family of
transcription factors.
• Mutations in, or deletions of, SHH (7q36) cause
holoprosencephaly（前脑无裂畸形）; Mutations
in PTCH (9q22) result in Gorlin syndrome;
Mutations in GLI3 (7p13) cause Pallister-Hall and
Grieg syndromes.
Homeobox (HOX) Genes
• Proteins from homeobox-containing (or HOX) genes
are important transcription factors that activate and
repress batteries of downstream genes. At least 35
downstream targets are known.
• Drosophila has 8 Hox genes arranged in a single
cluster.
• Humans, as in most vertebrates, there are 4
homeobox gene clusters containing a total of
39 HOX genes.
• E.g., Mutations in HOXA13 cause a rare condition
known as the hand-foot-genital syndrome.
Homeobox（同源〔异型〕框）refers to nucleic acid.
Homeodomain（同源〔异型〕域）refers to protein.
The homeodomain is a 60 aa helixturn-helix DNA-binding domain
Define
Hox,conserved
homeobox
that
is very
during
evolution. It fits into the major
groove of the DNA.
The term homeobox is reserved for the nucleic acid sequences
that encode homeodomains. Since they are highly conserved,
and can be detected by low-stringency hybridization across
species.
Edward B. Lewis
Homeotic genes specify body segment identity in Drosophila.
Lewis predicted Hox genes would be duplicated.
Vertebrates have 4 Hox complexes, with about 10 genes each.
They display colinearity（共线性）:
a) Spatial（空间）colinearity: the more anteriorly（前部）
expressed genes are in one end, the more posterior ones at the
other end of the gene complex.
b) Temporal（时间）colinearity: genes on one end of the
complex are expressed first, those on the other (posterior。后
部) end are turned on last.
c) Anterior Hox genes are activated sequentially by retinoic acid.
Hox genes can be aligned in 13 groups of paralogues (种内同源
基因。that were duplicated twice).
Paired-Box (PAX) Genes
• The paired-box is a highly conserved
DNA sequence that encodes a 130-aminoacid DNA-binding transcription
regulator domain.
• 9 PAX genes have been identified in mice
and humans.
SRY-type HMG (high-mobility
group) Box (SOX) Genes
• The SOX genes are transcription regulators
and are expressed in specific tissues during
embryogenesis.
• E.g., SOX1, SOX2, and SOX3 are expressed in
the developing mouse nervous system.
• Mutations in SOX10 on chromosome 22 cause
a rare form of Waardenburg syndrome.
T-Box (TBX) Genes
• This gene, which is also known as Brachyury
（鼠短尾突变体表型）, encodes a
transcription factor that contains both
activator and repressor domains.
• E.g., Loss-of-function mutations
in TBX3 cause the ulnar（尺骨）-mammary
syndrome.
Zinc Finger Genes
• The zinc finger refers to a finger-like loop
projection consisting of a series of four amino
acids that form a complex with a zinc ion.
• Genes that contain a zinc finger motif act as
transcription factors through binding of the
zinc finger to DNA.
Signal Transduction ('Signaling')
Genes
• Signal transduction is the process whereby
extracellular growth factors regulate cell division
and differentiation by a complex pathway of
genetically determined intermediate steps.
The RET Proto-oncogene
• Gain-of-function mutations, whether inherited
or acquired, are found in a high proportion of
thyroid cancers.
• Loss-of-function mutations in RET have been
identified in ~50% of familial cases of
Hirschsprung disease, in which there is failure
of migration of ganglionic cells to the
submucosal and myenteric plexuses of the large
bowel.
FGF Receptors
The Pharyngeal Arches（咽弓）
• The pharyngeal (or branchial) arches
correspond to the gill system of lower
vertebrates and appear in the fourth and fifth
weeks of development.
• Five (segmented) pharyngeal arches in humans
arise lateral to the structures of the head and
each comprises cells from the three germ layers
and the neural crest.
Acknowledge（PPT特别鸣谢！）
• UCLA David Geffen School of Medicine
• www.medsch.ucla.edu/ANGEL/
• Prof. Robertis E (UCLA), et al.