Molecular and Cellular Therapies for Motor Neuron Diseases

318 Pages·2017·12.357 MB·English

by  Nicholas M. Boulis, Deirdre O'Connor and Anthony Donsante (Eds.)

MOLECULAR AND CELLULAR
THERAPIES FOR MOTOR
NEURON DISEASES
MOLECULAR
AND CELLULAR
THERAPIES FOR
MOTOR NEURON
DISEASES
Edited by
Nicholas Boulis, Deirdre O’Connor
and Anthony Donsante
Emory University, Atlanta, GA, United States
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List of Contributors
N. Boulis Emory University, Atlanta, GA, United States
R. Bowser St Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
A.H.M. Burghes The Ohio State University, Columbus, OH, United States
K.S. Chen University of Michigan, Ann Arbor, MI, United States
M. Collins St Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
S. Corti University of Milan, Milan, Italy; IRCCS Foundation Ca’ Granda
Ospedale Maggiore Policlinico, Milan, Italy
A. Donsante Emory University, Atlanta, GA, United States
I. Faravelli University of Milan, Milan, Italy; IRCCS Foundation Ca’ Granda
Ospedale Maggiore Policlinico, Milan, Italy
E.L. Feldman University of Michigan, Ann Arbor, MI, United States
J.D. Glass Emory University, Atlanta, GA, United States
L. Karumbaiah The University of Georgia, Athens, GA, United States
K.P. Kenna University of Massachusetts Medical School, Worcester, MA, United
States
J.E. Landers University of Massachusetts Medical School, Worcester, MA,
United States
C.L. Lorson University of Missouri, Columbia, MO, United States
B.J. Mader Emory University, Atlanta, GA, United States
M.J. Magnussen Emory University, Atlanta, GA, United States
A. McDonough Emory University, Atlanta, GA, United States
V.L. McGovern The Ohio State University, Columbus, OH, United States
M.R. Miller University of Missouri, Columbia, MO, United States
D.M. O’Connor Emory University, Atlanta, GA, United States
E.Y. Osman University of Missouri, Columbia, MO, United States
S.L. Stice The University of Georgia, Athens, GA, United States
R.L. Swetenburg The University of Georgia, Athens, GA, United States
N. Ticozzi IRCCS Istituto Auxologico Italiano, Milan, Italy; ‘Dino Ferrari’
Center – Università degli Studi di Milano, Milan, Italy
L. Urquia Emory University, Atlanta, GA, United States
xi
Acknowledgment
This book is dedicated to the people diagnosed with this disease and
their families, who have refused to take no for an answer and have
dedicated themselves to raising funding for research and volunteering
for risky groundbreaking clinical trials, including Josh Thompson and his
family, Ed Tesoro, Ted Harada, and Christina Clark.
xiii
C H A P T E R
1
Molecular and Extracellular
Cues in Motor Neuron
Specification and Differentiation
R.L. Swetenburg, S.L. Stice and L. Karumbaiah
The University of Georgia, Athens, GA, United States
O U T L I N E
Introduction 2
Specification of Neuroectoderm 3
Spinal Cord Patterning 3
The Motor Neuron Progenitor Domain and Initial Neurogenesis 5
Molecular Programs in Newborn Motor Neurons 5
Migration 6
Motor Neuron Subtypes and Targets 6
Somatic Motor Neurons 7
Visceral Motor Neurons 8
Axon Targeting 9
Extracellular Matrix and the Nervous System 10
Collagen 10
Laminin 10
Molecular and Cellular Therapies for Motor Neuron Diseases.
1
DOI:http://dx.doi.org/10.1016/B978-0-12-802257-3.00001-8 © 2017 Elsevier Inc. All rights reserved.
2
1. MOLECULAR AND EXTRACELLULAR CUES
Fibronectin 11
Proteoglycans and Glycosaminoglycans 11
Chondroitin Sulfate Proteoglycans 12
Heparan Sulfate Proteoglycans 12
Hyaluronic Acid 12
Motor Neuron Cell Death 13
The Glial Switch 13
Generating Motor Neurons From Pluripotent Stem Cells 14
Generating Oligodendrocyte Precursor Cells From Pluripotent
Stem Cells 17
Conclusion 17
References 18
INTRODUCTION
Motor neurons (MN) are a diverse group of cells without which com-
plex life would not be possible. MNs are responsible for integrating sig-
nals from the brain and the sensory systems to control voluntary and
involuntary movements. Though MNs can be split into cranial and spinal
subsets, this chapter will focus on spinal MNs, as they are a key target of
disease and injury. As such, MNs are the focus of regenerative efforts to
alleviate these public health burdens. During late gastrulation and neu-
rulation, the developing spinal cord, termed the neural tube, is patterned
into distinct progenitor domains. MNs are specified from progenitors in
the ventral neural tube. Once specified, newly born MNs are further speci-
fied into columns, pools, and subtypes, forming a unique topography.
From these columns and pools, axons reach out to their targets under
varying guidance cues. All MNs are cholinergic cells which integrate with
the motor control circuit, the sensory system, and their outlying targets
to control movement. MNs are unique in that their targets lie outside the
central nervous system (CNS), meaning that they require novel methods
for seeking out and synapsing on them. Here, we present an overview of
MN differentiation and development. We will focus mainly on signaling
events, transcription factor markers, and the extracellular matrix (ECM) as
MOLECULAR AND CELLULAR THERAPIES FOR MOTOR NEURON DISEASES
3
SPINAL CORD PATTERNINg
they pertain to MN development. These cells are targets of permanent and
often deadly diseases including amyotrophic lateral sclerosis, spinal mus-
cular atrophy, multiple sclerosis, and injuries such as spinal cord injury.
Only by understanding how these cells progress through development
can we understand how to treat these maladies which currently have
little hope of a cure. Further, by decoding the major events and players in
development, we can better recapitulate them in vitro for cell replacement
therapy, or harness the underlying principles for regeneration in the adult.
Given the growing importance of the MN–glia interaction in a number of
neurodegenerative diseases, we will also discuss the initial specification of
oligodendrocyte precursor cells (OPCs) in detail, as they share a common
progenitor with MNs.
SPECIFICATION OF NEUROECTODERM
Vertebrate embryos specify the ectoderm in late gastrulation. This germ
layer will become the epidermis and the nervous system. The anterior
neural ectoderm is distinguished from the epidermis by its inability to
bind bone morphogenic proteins (BMPs) due to the inhibitors secreted
from the Spemann–Mangold organizer region of the gastrula.1 These
inhibitors—noggin, chordin, and follistatin—bind and neutralize the
effects of BMPs, creating a permissive transcriptional environment for
neural progression.2–5 Posteriorly, the neural plate is specified by fibro-
blast growth factors (FGFs) and Wingless-related integration site (Wnt)
proteins that also suppress BMP activity.6 Additionally, retinoid signaling
from the paraxial mesoderm specifies the cells of the future spinal cord.7
This newly specified neural plate then thickens as cells proliferate and
invaginates through the convergent extension, forming the neural groove.
The neural groove forms hinge points which will ultimately close to form
the neural tube – the precursor for the entire CNS.8 For an in-depth review,
see Massarwa et al.9
SPINAL CORD PATTERNING
The spinal cord is a two-way information conduit that connects the
brain with the sensory and motor systems. To do this, it must generate
a highly diverse set of neurons during development. The neural tube
provides a three-dimensional template which is patterned by gradients
of morphogens to generate this diversity. The early neural tube is com-
posed of multipotent neural stem cells expressing Sex determining region
Y box 1 (Sox1).10 The dorsal neural tube will generate cells linking the
MOLECULAR AND CELLULAR THERAPIES FOR MOTOR NEURON DISEASES
4
1. MOLECULAR AND EXTRACELLULAR CUES
CNS to the sensory peripheral nervous system (PNS). The ventral neural
tube will ultimately give rise to the motor control circuit responsible for
controlling MNs. Bone morphogenetic proteins specify the dorsal portion
of the neural tube, including neuronal subtypes involved in integration
of the peripheral sensory nervous system. Ventrally, an initial wave of
Sonic hedgehog (Shh) from the notochord patterns the cells into distinct
progenitor domains.11 These domains arise due to cross-repressive actions
of two types of transcription factors downstream of Shh signaling: Type I
transcription factors are repressed at threshold Shh concentrations, while
Type II are expressed below threshold Shh concentrations11 (Fig. 1.1A).
The type I transcription factor paired box protein 6 (Pax6) represses the
activity of type II homeobox protein Nkx2.1. Similarly, type II homeobox
Nkx6.1 cross-represses developing brain homeobox 2 (Dbx2).11 The most
ventral progenitor domain is the floor plate, which is induced to secrete
Shh in a second wave of patterning, followed by the progenitor domains
p3, pMN, p2, p1, and p0 (Fig. 1.1B). The combinatory actions of these
two classes of proteins yield the five spatially distinct ventral progenitor
domains.
FIGURE 1.1 A gradient of sonic hedgehog drives progenitor domain formation in the
ventral neural tube. (A) Sonic hedgehog (Shh) signaling from the notochord (NC) drives
Class I transcription factors and represses Class II transcription factors at threshold levels.
These transcription factors cross-repress to form sharply delineated boundaries. The class
I Nkx2.2 represses the class II Pax6, while the Class I Nx6.1 represses Dbx2. (B) This cross-
repression leads to five distinct domains: FP (floor plate), p3, pMN (motor neuron progeni-
tor), p2, p1, and p0. p, progenitor.
MOLECULAR AND CELLULAR THERAPIES FOR MOTOR NEURON DISEASES
5
MOLECULAR PROgRAMS IN NEwbORN MOTOR NEURONS
THE MOTOR NEURON PROGENITOR DOMAIN
AND INITIAL NEUROGENESIS
The MN progenitor (pMN) domain is responsible for generating MNs.
In mice and chick models, this domain is identified by the expression
of the homeobox transcription factors Nkx6.1 and Pax6 and the basic
helix–loop–helix (bHLH) oligodendrocyte transcription factor 2 (Olig2).12
Olig2 expression is obligate for MN specification, as Olig2null mice fail to
generate MNs.13 Initially, Olig2 plays a key role in progenitor prolifera-
tion; however, it also drives the expression of neurogenin 2 (Ngn2),14 a
key neural determinant. The first murine MNs are born around E9.5.13
The homeobox transcription factor Nkx2.2, important for the glial switch
and a marker for p0 cells, shows variable expression in humans com-
pared to mouse and chick models: the human pMN domain appears to
include both Olig2+/Nkx2.2− as well as Olig2+/Nkx2.2+ cells.15 This
could potentially add to the diversity of human MNs.
MOLECULAR PROGRAMS IN NEWBORN
MOTOR NEURONS
As mentioned above, Olig2 drives Ngn2 expression. However, Ngn2
is ultimately responsible for cell cycle exit and neurogenesis,16,17 in direct
contrast to the role of Olig2. Once Ngn2 protein levels surpass those of
Olig2, cell cycle exit occurs and cells commit to the neuronal lineage.
Olig2 binds and sequesters the MN transcription factor homeobox gene 9
(Hb9, also called MNX1), which is necessary for MN development.17 LIM
homeobox gene Isl1 and LIM homeobox 3 (Lhx3) form a complex with
the nuclear LIM interactor which suppresses interneuron fate and speci-
fies MN.18 Along with Ngn2, this complex stimulates Hb9, which self-
stimulates its own expression,19 while forming a positive feedback loop
with Isl1. Isl1 and 2 work in concert to further specify MN cell fate.20 Lhx3
and Isl1 expressions are necessary for MN generation and the expression
of cholinergic genes common to all MNs.21 However, little is known about
potential negative feedback mechanisms in this differentiation process
that would limit MN number and organ size. We will discuss this further
in the Glial Switch section.
In summary, Shh secreted from notochord drives the expression of Pax6
and Nxk6.1, which in turn drive Olig2 expression. Olig2 expression delin-
eates a mitotic pMN progenitor. Olig2 induces the expression of Ngn2,
which is responsible for cell cycle exit, of Lhx3/Isl1 transcription factors,
as well as MN-specific Hb9 in newborn, postmitotic MNs (Fig. 1.2).
MOLECULAR AND CELLULAR THERAPIES FOR MOTOR NEURON DISEASES