Download 张咸宁-模块1-第2周

与发育相关的基因
张咸宁
[email protected]
Tel：13105819271; 88208367
Office: C303, Teaching 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本质上 abnormal developmental process
(e.g., cleft lip唇裂, polydactyly多指趾).
• Dysplasia发育异常 is a primary defect involving abnormal organization of
cells into tissue (e.g., vascular malformation血管畸形).
• 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腭裂)
• 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机械力. It usually occurs in the fetal
period, not in embryogenesis胚胎发生. It is a secondary alteration. It can
be extrinsic外在的, as in oligohydramnios羊水过少 (reduced amniotic
fluid), or intrinsic, as in congenital myotonic dystrophy强直性肌营养不良.
• 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破坏 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模式动物: Drosophila melanogaster
果蝇, frog, mouse, chick, zebra-fish斑马鱼…
• Transcription factors转录因子 can switch genes on
and off by activating or repressing gene expression.
• Fundamental embryological processes: induction
诱导 (the process in which extracellular signals胞
外信号 give rise to a change from one cell fate细胞
结局 to another in a particular group of cells),
segmentation分节, migration迁移, differentiation
分化, and PCD (apoptosis细胞凋亡).
• These processes are mediated by growth factors生
长因子, cell receptors细胞受体, and chemicals
(morphogens形态发生素).
Transcription factors转录因子
• These gene regulatory proteins调控蛋白
have a transcriptional activation domain
转录激活功能域 and a DNA-binding
domain DNA结合域.
• 4 types of DNA-binding domain: helixturn-helix螺旋-转角-螺旋, zinc finger锌
指, leucine zipper亮氨酸拉链, helix-loophelix螺旋-环-螺旋.
1.Early Patterning早期图式发育
• Induction of the mesoderm中胚层的诱导-the initiation,
maintenance, and subsequent patterning of this layerinvolves several key families of signaling factors.
• The Nodal family is involved in initiation, FGFs
(fibroblast growth factors成纤维细胞生长因子) and
WNTs (wingless) are involved in maintenance, and
BMPs (bone morphogenetic proteins骨形态发生蛋白)
are involved in patterning the mesoderm.
• The WNT pathway has two main branches: β-catenindependent (canonical标准的) , independent of βcatenin.
• E.g., Mutated WNT10A in man results in a form of
ectodermal dysplasia外胚层发育不良症 (odontoonychodermal dysplasia).
2.The TGF-β (transforming growth
factor-β ) Superfamily超家族 in
Development and Disease
• 33 members of this cytokine family细胞因子家族.
• 2 groups: (1) the BMPs, (2) the TGF-βs, activins,
nodal, and myostatin筒箭毒碱, acting through
various SMAD proteins.
• Regulation of the cell cycle, cell migration, cell size,
gastrulation原肠胚形成 and axis枢椎 specification,
and metabolic processes.
• In relation to health and disease, there are
consequences for immunity, cancer, heart disease,
diabetes, and Marfan syndrome.
A summary of
biological
responses to
TGF family
signaling. The
range of
processes that
come under
the influence
of this super
family is very
broad.
3.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振荡时钟’-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尾芽 region in a rostral嘴的
direction and has a key role in the process leading to the
defining of somite体节 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.
Somatogenesis
and Notch-Delta
pathway. T-box
genes have a role
in PSM
specification,
whereas the
segmentation
clock depends on
oscillation, or
cycling, genes that
are important in
somite boundary
formation where
genes of the
Notch-Delta
pathway establish
rostro-caudal
polarity. HOX
genes have a
global function in
establishing
somite identity
along the entire
rostro-caudal axis.
4.The Sonic Hedgehog-Patched GLI
Pathway
• The Sonic hedgehog gene (SHH) induces cell
proliferation增殖 in a tissue-specific distribution and
is expressed in the notochord脊索, 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.
The Sonic hedgehog
(Shh)-Patched (Ptch)-Gli
pathway and connection
with disease. Different
elements in the
pathway act as activators
(arrows) or inhibitors
(bars). The Shh protein is
initially cleaved to an
active N-terminal form,
which is then modified by
the addition of cholesterol.
The normal action of Ptch
is to inhibit Smo, but
when Ptch is bound by
Shh this inhibition is
removed and the
downstream signaling
proceeds. CREBBP,
cAMP response elementbinding binding protein.
5. Homeobox (HOX) 同源框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果蝇 has 8 Hox genes arranged in a single
cluster.
• Humans, as in most vertebrates脊椎动物, 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-genitalsyndrome 手-足-外生
殖器综合征.
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
helix-turn-helix DNA-binding
Define Hox,
domain
that ishomeobox
very conserved
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-stringencyhybridization低严谨杂
交 across species.
Edward B. Lewis
Homeotic genes specify body segment identity in Drosophila.
Lewis predicted Hox genes would be duplicated.
A：Drosophila has eight Hox genes in a single cluster whereas there are 39 HOX genes
in humans, arranged in four clusters located on chromosomes 7p, 17q, 12q, and 2q for
the A, B, C, and D clusters, respectively. B：Expression patterns of Hox and HOX
genes along the rostro-caudal axis in invertebrates and vertebrates, respectively. In
vertebrates the clusters are paralogous and appear to compensate for one another.
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.
6. Paired-Box (PAX) Genes
• The paired-box is a highly conserved高度
保守 DNA sequence that encodes a 130amino-acid DNA-binding transcription
regulator domain.
• 9 PAX genes have been identified in mice
and humans.
7.SRY-type HMG (high-mobility高泳
动 group) Box (SOX) Genes
• The SOX genes are transcription regulators
and are expressed in specific tissues during
embryogenesis胚胎发生.
• 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.
8. 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乳房
syndrome.
9. Zinc Finger Genes
• The zinc finger refers to a finger-like loop
projection突出物 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.
10.Signal Transduction信号转导
('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.
（1）The RET Proto-oncogene
• Gain-of-function mutations, whether inherited
or acquired, are found in a high proportion of
thyroid cancers（多发性内分泌腺瘤2型/MEN
2）.
• 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.
（2）FGF Receptors
A young child with
achondroplasia软骨
发育不全
11.The Pharyngeal Arches咽弓
• The pharyngeal (or branchial) arches
correspond to the gill system鳃系 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.