Multiple Functions of Notch Signaling
7 during Early Embryogenesis
Silvia L. López
CONTENTS
7.1. Historical Background ................................................................................................................................................. 77
7.2. The Notch Pathway ...................................................................................................................................................... 77
7.2.1. Canonical Notch Signaling ............................................................................................................................. 78
7.2.2. Non-Canonical Notch Signaling ..................................................................................................................... 78
7.3. Notch Signaling during Xenopus Embryogenesis ........................................................................................................ 78
7.3.1. Establishing the Dorsal-Ventral Axis .............................................................................................................. 90
7.3.2. Germ Layer Formation ................................................................................................................................... 90
7.3.3. Dorsal Midline Tissues ................................................................................................................................... 98
7.3.4. Primary Neurogenesis ..................................................................................................................................... 99
7.3.5. Neural Plate Border and Midbrain-Hindbrain Boundary .............................................................................. 102
7.3.6. Somitogenesis ............................................................................................................................................... 107
7.4. Future Directions ....................................................................................................................................................... 116
References ............................................................................................................................................................................ 117
7.1. HISTORICAL BACKGROUND
The Notch pathway is a key cell-cell communication
mechanism utilized during metazoan development. Its
outcome depends on cell context: it can inhibit or promote
cell fates, cell proliferation, or cell death through ligandreceptor signaling between neighboring cells (Kopan
and Ilagan, 2009). The story of Notch began when John
S. Dexter, in Thomas Hunt Morgan’s laboratory, found
a mutant phenotype in Drosophila with characteristic
serrations at the wings’ ends, which he called Perfect
Notched (Dexter, 1914; Bridges and Morgan, 1916). This
was caused by the disruption of a dominant sex-linked
gene resulting in male lethality, which received the name
Notch in subsequent publications (Bridges and Morgan,
1916; Morgan, 1917; Mohr, 1919). In the 1930s, Donald
Poulson studied the lethal phenotype and noticed aberrant germ layer development (Poulson, 1937). This was
later interpreted as a switch in ectodermal cell fate from
dermoblast to neuroblast, since different mutant alleles
of Notch, Delta, mastermind, neuralized, Enhancer of
split, almondex, and big brain resulted in nervous system
hypertrophy at the expense of the epidermis (Lehmann
et al., 1983). These so-called “neurogenic” gene s are all
involved in the Notch pathway and have vertebrate counterparts (fybase.org; Lehmann et al., 1983; Thurmond
et al., 2019).
Seven decades after Dexter’s discovery, the f y Notch
gene was cloned (Artavanis-Tsakonas et al., 1983), and
the frst vertebrate homologue, notch1, was isolated from
Xenopus laevis (Coffman et al., 1990). Frog experiments
using a construct lacking the extracellular domain provided the frst clues that the Notch intracellular domain
(NICD) mediates signal transduction (Coffman et al.,
1993). This truncation resulted in a gain-of-function phenotype that affected germ layer development. Cloning
the Xenopus gene encoding a ligand, Delta-like-1 (Dll1),
demonstrated that Delta/Notch signaling plays a neurogenic role in vertebrates through lateral inhibition, as
previously defned in Drosophila (Chitnis et al., 1995;
Campos-Ortega, 1985; Lewis, 1998). Because of its relative simplicity, primary neurogenesis in Xenopus provided an ideal paradigm for Notch pathway research and
for unraveling the molecular and cellular bases of vertebrate neural development. Since these ground-breaking
studies, the accessibility of Xenopus embryos has made
them an outstanding model for revealing the role of the
Notch pathway in multiple developmental processes and
for testing heterologous molecules from different species
such as mouse and human, wild-type and mutant forms
of pathway components, and to study their function and
biochemical modulation in vivo (Ali et al., 2014; Hein et
al., 2015; Oswald et al., 2016).
7.2. THE NOTCH PATHWAY
Most of what is known about Notch signaling can be categorized in either canonical or non-canonical pathways.
DOI: 10.1201/9781003050230-8
77
7 during Early Embryogenesis
Silvia L. López
CONTENTS
7.1. Historical Background ................................................................................................................................................. 77
7.2. The Notch Pathway ...................................................................................................................................................... 77
7.2.1. Canonical Notch Signaling ............................................................................................................................. 78
7.2.2. Non-Canonical Notch Signaling ..................................................................................................................... 78
7.3. Notch Signaling during Xenopus Embryogenesis ........................................................................................................ 78
7.3.1. Establishing the Dorsal-Ventral Axis .............................................................................................................. 90
7.3.2. Germ Layer Formation ................................................................................................................................... 90
7.3.3. Dorsal Midline Tissues ................................................................................................................................... 98
7.3.4. Primary Neurogenesis ..................................................................................................................................... 99
7.3.5. Neural Plate Border and Midbrain-Hindbrain Boundary .............................................................................. 102
7.3.6. Somitogenesis ............................................................................................................................................... 107
7.4. Future Directions ....................................................................................................................................................... 116
References ............................................................................................................................................................................ 117
7.1. HISTORICAL BACKGROUND
The Notch pathway is a key cell-cell communication
mechanism utilized during metazoan development. Its
outcome depends on cell context: it can inhibit or promote
cell fates, cell proliferation, or cell death through ligandreceptor signaling between neighboring cells (Kopan
and Ilagan, 2009). The story of Notch began when John
S. Dexter, in Thomas Hunt Morgan’s laboratory, found
a mutant phenotype in Drosophila with characteristic
serrations at the wings’ ends, which he called Perfect
Notched (Dexter, 1914; Bridges and Morgan, 1916). This
was caused by the disruption of a dominant sex-linked
gene resulting in male lethality, which received the name
Notch in subsequent publications (Bridges and Morgan,
1916; Morgan, 1917; Mohr, 1919). In the 1930s, Donald
Poulson studied the lethal phenotype and noticed aberrant germ layer development (Poulson, 1937). This was
later interpreted as a switch in ectodermal cell fate from
dermoblast to neuroblast, since different mutant alleles
of Notch, Delta, mastermind, neuralized, Enhancer of
split, almondex, and big brain resulted in nervous system
hypertrophy at the expense of the epidermis (Lehmann
et al., 1983). These so-called “neurogenic” gene s are all
involved in the Notch pathway and have vertebrate counterparts (fybase.org; Lehmann et al., 1983; Thurmond
et al., 2019).
Seven decades after Dexter’s discovery, the f y Notch
gene was cloned (Artavanis-Tsakonas et al., 1983), and
the frst vertebrate homologue, notch1, was isolated from
Xenopus laevis (Coffman et al., 1990). Frog experiments
using a construct lacking the extracellular domain provided the frst clues that the Notch intracellular domain
(NICD) mediates signal transduction (Coffman et al.,
1993). This truncation resulted in a gain-of-function phenotype that affected germ layer development. Cloning
the Xenopus gene encoding a ligand, Delta-like-1 (Dll1),
demonstrated that Delta/Notch signaling plays a neurogenic role in vertebrates through lateral inhibition, as
previously defned in Drosophila (Chitnis et al., 1995;
Campos-Ortega, 1985; Lewis, 1998). Because of its relative simplicity, primary neurogenesis in Xenopus provided an ideal paradigm for Notch pathway research and
for unraveling the molecular and cellular bases of vertebrate neural development. Since these ground-breaking
studies, the accessibility of Xenopus embryos has made
them an outstanding model for revealing the role of the
Notch pathway in multiple developmental processes and
for testing heterologous molecules from different species
such as mouse and human, wild-type and mutant forms
of pathway components, and to study their function and
biochemical modulation in vivo (Ali et al., 2014; Hein et
al., 2015; Oswald et al., 2016).
7.2. THE NOTCH PATHWAY
Most of what is known about Notch signaling can be categorized in either canonical or non-canonical pathways.
DOI: 10.1201/9781003050230-8
77