Seminars in Developmental Biology最新文献

In this review we summarize evidence for the involvement of neutrophins in the regulation of neurite outgrowth in the peripheral nervous system. Recent studies have shown that many neurons at early developmental stages respond to NT3 by increased survival and morphological differentiation in vitro. In addition, NT3 mRNA can be detected at this time in embryonic tissues trespassed by outgrowing neurites. Later during development, the NT3 response may be lost and replaced by a NGF response. The data show that an early NGF-independent, NT3-sensitive and a late NGF-responsive period can be distinguished for different developing peripheral neurons in vitro and raise the possibility that neurite outgrowth may be influenced by the different neutrophins, acting at distinct developmental periods in vivo.

The formation of axonal connections in the nervous system involves cell-specific decisions of the growth cone. In this article we examine the contribution of early fate decisions to axonal pathfinding. Evidence is accumulating that different neuronal cell types in the cerebral cortex are specified during their final mitosis. It would seem that cortical projection neurons are pre-specified to choose particular pathways, since the newly generated neurons send out their axons in the correct direction from the onset of outgrowth. Pathfinding decisions that are made much later during development, such as the recognition of specific target-derived chemoattractants and the retraction of inappropriate axon collaterals, also seem to be at least partially pre-specified at much earlier developmental stages. Hence, the early determination of a neuron's phenotype includes the specification of axonal growth occuring over a protracted phase of development. Understanding more about the regulative events targeted to the growth cone should help us to unravel the decisions made by this specialized neuronal organelle.

Four interactive processes—adhesion, guidance, migration and growth—combine to direct the axonal growth cone to its targets. It is becoming clear that the sensors of the external environment, the axonal receptors and adhesion molecules, activate second messenger systems in the growth cone. This allows a cytoplasmic integration of guidance signals acting upon the growth cone, that feeds back upon the adhesion molecules and the cytoskeleton to select the direction of growth. Movement is primarily generated by the actin microfilaments, growth is dependent upon the microtubules. This review examines the interdependence of these processes during the initial phase of axon elongation, using examples from insects to mammals.

Prader-Willi (PWS) and Angelman (AS) syndromes illustrate a disease paradigm of genomic imprinting, an epigenetic modification of DNA that results in parent-of-origin specific expression during embryogenesis and in the adult. From genetic data, at least two imprinted genes may be required for the classical PWS phenotype, whereas AS probably involves a single imprinted gene, and rare familial forms of both disorders involve imprinting mutations. In addition, the nonimprinted P gene is associated with pigmentation disorders in PWS, AS and oculocutaneous albinism. Identification of new genes, delineation of small deletions in unique patients, and direct screening for imprinted sequences, should soon identify candidate genes for PWS and AS. The mechanism of imprinting involves DNA methylation and replication timing, and appears to include multiple imprinted genes within a large imprinted domain. Imprinting of these genes may be regulated in cis, by an imprinting control element (ICE). Future studies can be expected to unravel the gene identities and imprinting mechanisms involved in these fascinating disorders; ultimately it may be possible to reactivate imprinted gene expression as a therapeutic approach.

Classically, DiGeorge syndrome patients have congenital heart defects, particularly involving the outflow tract, hypocalcaemia, cell-mediated immune deficiency, learning or behavioural problems, craniofacial dysmorphism and hemizygosity for a region of human chromosome 22q11. This chromosomal abnormality is now known to cause other syndromal defects and apparently isolated congenital heart disease. Although most patients have a large deletion, at least 2 Mb, a critical region of 300 kbp has been defined. Within this region a putative transcriptional regulator called TUPLE-1 has been identified. TUPLE-1 is proposed as a candidate gene for the 22q11 haploinsufficiency syndromes.

Holoprosencephaly is a common developmental defect of the forebrain and midface in humans. Clinical expression is variable, extending in unbroken sequence from a small brain with a single cerebral ventricle and cyclopia to clinically unaffected carriers in familial holoprosencephaly. Significant aetiological heterogeneity in holoprosencephaly has been demonstrated including both genetic and environmental causes. Genetic approaches, such us positional cloning of genes involved in holoprosencephaly will result in a better understanding of normal development of the brain and face and, ultimately, elucidate the basic genetic defects which programme the abnormal formation seen in holoprosencephaly.

Pax genes encode the highly conserved 128 amino acid paired domain, first seen in the Drosophila paired gene. Humans and mice each have nine Pax genes, scattered across the genome. They are mostly expressed in the developing nervous system, with some specific expression in adults, and they control important aspects of cell growth and differentiation. Development is sensitive to Pax gene dosage. Loss of function mutations in PAX3 and PAX6 cause Waardenburg syndrome and aniridia, respectively, while a gain of function mutation in which PAX3 forms a chimaeric gene by fusion to the FKHR transcription factor causes the paediatric tumour alveolar rhabdomyosarcoma. Pax gene mutations are likely to underlie other developmental syndromes and cancers.