Regeneration in the Era of Functional Genomics and Gene Network Analysis

Abstract

What gives an organism the ability to regrow tissues and to recover function where another organism fails is the central problem of regenerative biology. The challenge is to describe the mechanisms of regeneration at the molecular level, delivering detailed insights into the many components that are cross-regulated. In other words, a broad, yet deep dissection of the system-wide network of molecular interactions is needed. Functional genomics has been used to elucidate gene regulatory networks (GRNs) in developing tissues, which, like regeneration, are complex systems. Therefore, we reason that the GRN approach, aided by next generation technologies, can also be applied to study the molecular mechanisms underlying the complex functions of regeneration. We ask what characteristics a model system must have to support a GRN analysis. Our discussion focuses on regeneration in the central nervous system, where loss of function has particularly devastating consequences for an organism. We examine a cohort of cells conserved across all vertebrates, the reticulospinal (RS) neurons, which lend themselves well to experimental manipulations. In the lamprey, a jawless vertebrate, there are giant RS neurons whose large size and ability to regenerate make them particularly suited for a GRN analysis. Adding to their value, a distinct subset of lamprey RS neurons reproducibly fail to regenerate, presenting an opportunity for side-by-side comparison of gene networks that promote or inhibit regeneration. Thus, determining the GRN for regeneration in RS neurons will provide a mechanistic understanding of the fundamental cues that lead to success or failure to regenerate.

CRISPR/Cas9-mediated mutagenesis in the sea lamprey, Petromyzon marinus: a powerful tool for understanding ancestral gene functions in vertebrates

“…However, due to the inaccessibility of hagfish, which live and spawn on the ocean floor (Ota et al, 2007), most studies of agnathan biology have focused on lampreys. Work on lamprey embryos, larvae and adults has provided important insights into the evolution of key vertebrate features including the adaptive immune system (Pancer et al, 2004), the endocrine system (Sower et al, 2009;Close et al, 2010), regenerative capacity (Smith et al, 2011), the head skeleton (McCauley and Bronner-Fraser, 2006) and large-scale gene duplications (Smith et al, 2013). There is also much interest in understanding lamprey biology with the goal of conserving native lamprey species and controlling invasive lampreys (reviewed by Sower, 2003).…”

Theranostic Probes for Targeting Tumor Microenvironment: An Overview

“…To improve the imaging modality, positive contrast enhancement is achieved using gadolinium-tetraazacyclododecane tetraacetic acid monoamide conjugate of 2-nitroimidazole (GdDO3NI). Not only can it measure the oxygen deficiency in tumors, it can observe the area with low blood vessel perfusion of a xenograft rat model suffering from prostate cancer [28].…”

“…However, the available probes are not used in clinical trials so far. Furthermore, another pH probe like Chemical Exchange Saturation Transfer (CEST) is used to image breast cancer in xenograft model with clinically trialed contrast agents of CT such as iopromide [28]. It can determine the correlation between the amide protons of iopromide and the level of pH.…”

A primer on regeneration

“…Even repair and regeneration of single cells, whether free-living (e.g. protozoan Stentor) or as part of complex structures (axonal regeneration in spinal cord neurons of lamprey), are being analyzed with a molecular lens (Slabodnick and Marshall, 2014;Smith et al, 2011). The study of regeneration not only reveals the secrets of this fascinating phenomenon, it uncovers developmental pathways of differentiation, molecules that influence the longevity of cells, roles of programmed cell death, and the control of cellular proliferation.…”